WO2013026553A1 - Composition comprising edoxaban - Google Patents

Composition comprising edoxaban Download PDF

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Publication number
WO2013026553A1
WO2013026553A1 PCT/EP2012/003512 EP2012003512W WO2013026553A1 WO 2013026553 A1 WO2013026553 A1 WO 2013026553A1 EP 2012003512 W EP2012003512 W EP 2012003512W WO 2013026553 A1 WO2013026553 A1 WO 2013026553A1
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WO
WIPO (PCT)
Prior art keywords
edoxaban
dosage form
composition
forming agent
composition according
Prior art date
Application number
PCT/EP2012/003512
Other languages
French (fr)
Inventor
Ralph Stefan
Dominique Meergans
Original Assignee
Ratiopharm Gmbh
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 Ratiopharm Gmbh filed Critical Ratiopharm Gmbh
Publication of WO2013026553A1 publication Critical patent/WO2013026553A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems

Definitions

  • composition comprising Edoxaban
  • the invention relates to compositions containing edoxaban and a C0 2 -forming agent, preferably for immediate release.
  • the invention also relates to methods of preparing dosage forms containing said compositions.
  • Edoxaban is reported to be a member of the so-called "Xaban-group" and as such to be a low molecular inhibitor of the enzyme factor Xa, participating in the blood coagulation system. Therefore, edoxaban is classified as an antithrombotic drug and its possible medical indications are reported to be treatment of thrombosis and thrombosis prophylaxis after orthopaedic operations, such as total hip replacement, as well as for stroke prevention in patients with atrial fibrillation, the prophylaxis of the acute coronary syndrome and the prophylaxis after thrombosis and pulmonary embolism.
  • edoxaban N'-(5-chloropyridin-2-yl)-N-[(15,2 ⁇ ,4S)-4- (dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[l ,3]thiazolo[5,4-c]pyridine-2- carbonyl)amino]cyclohexyl]oxamide.
  • the chemical structure of edoxaban is shown in the formula (1) below:
  • EP 2 140 867 A 1 claims an edoxaban-containing pharmaceutical composition comprising a water-swelling additive and/or a sugar alcohol. Further, it is alleged that compositions comprising lactose or cornstarch do not have good dissolution properties. The claimed pharmaceutical compositions in EP 2 140 867 Al are considered to show good dissolution properties in a neutral aqueous medium as well. Tablets comprising said composition were produced by wet granulation.
  • the advantageous properties should be achieved even if (cheap) excipients like saccharose and cornstarch are used, which are described as disadvantageous in the prior art. Expensive processes like melt granulation should be avoided.
  • composition in particular a pharmaceutical composition, containing edoxaban and a C0 2 -forming agent.
  • the composition can be further processed into a dosage form, preferably by direct compression.
  • composition and or dosage form of the present invention can be free of sugar alcohols and has superior dissolution rates and superior permeability, resulting in an excellent bioavailability of the active pharmaceutical ingredient. Further, even when wet granulation was avoided, a superior content uniformity of the drug was achieved, which ensured that the appropriate dose was applied to the patient. It was further found that the composition/dosage form of the present invention was very stable over a prolonged period of time.
  • a subject of the present invention is a composition containing edoxaban and a C0 2 -forming agent.
  • Another subject of the invention is a method for preparing a composition and/or dosage form containing edoxaban and a C0 2 -forming agent comprising the steps of mixing edoxaban, C0 2 -forming agent and optionally one or more pharmaceutical excipient(s),
  • step (a2) optionally granulating the mixture from step (al), and
  • step (a3) processing the mixture resulting from step (al) or the granulates from (a2) into a dosage form
  • edoxaban comprises N'-(5- chloropyridin-2-yl)-N-[( 15 5 2i?,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7- dihydro-4H-[l ,3]thiazolo-[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide in accordance with formula (1 ) above.
  • the term “edoxaban” comprises all the pharmaceutically acceptable salts, hydrates and/or solvates thereof, for example edoxaban tosylate.
  • edoxaban is used in form of the free base.
  • edoxaban is used in the form of the tosylate monohydrate salt.
  • ratios or amounts of edoxaban generally refer to the ratio or amount of edoxaban in form of the free base.
  • composition or the dosage form of the present invention can comprise edoxaban as the sole pharmaceutical active agent.
  • composition or the dosage form of the present invention can comprise edoxaban in combination with further pharmaceutical active agent(s).
  • edoxaban preferably means edoxaban in crystalline form, i.e. preferably more than 90 % by weight of the edoxaban used is in crystalline form, especially preferred 100 %.
  • the average particle size (D 50 -value) of edoxaban can be from 0. 1 to 150 ⁇ , preferably from 0.15 to 100 ⁇ , more preferably from 0.2 to 75 ⁇ .
  • the edoxaban can be micronized edoxaban.
  • the expression "micronized edoxaban” is used in the context of this invention to designate particulate edoxaban, which generally has an average particle diameter (D 50 -value) of 0.1 to 20 ⁇ , preferably 0.3 to 10 ⁇ , more preferably 0.5 to 5 ⁇ and especially 1.0 to 4.0 ⁇ .
  • average particle diameter relates in the context of this invention to the D 50 value of the volume-average particle diameter determined by means of laser diffractometry.
  • a Malvern Instruments Mastersizer 2000 was used to determine the diameter (wet measurement, 2,000 rpm, ultrasonic 60 sec, preferably shading 4 to 13 %, preferably dispersion in liquid paraffin, evaluated according to the Fraunhofer method).
  • the average particle diameter which is also referred to as the D 5 o-value of the integral volume distribution, is defined in the context of this invention as the particle diameter, at which 50 % by volume of the particles have a smaller diameter than the diameter which corresponds to the D 0 value. Similarly, 50 % by volume of the particles then have a larger diameter than the D 50 value.
  • the Di 0 -value of the integral volume distribution is defined as the particle diameter at which 10 % by volume of the particles have a smaller diameter than the diameter which corresponds to the Di 0 -value.
  • the Dio-value of the integral volume distribution is from 0.01 to 7 ⁇ , preferably from 0.05 to 5 ⁇ , more preferably from 0.1 to 3.5 ⁇ and especially from 0.5 to 1.5 ⁇ .
  • the Dgo-value of the integral volume distribution is defined as the particle diameter at which 90 % by volume of the particles have a smaller diameter than the diameter which corresponds to the D9 0 -value.
  • the Devalue of the integral volume distribution is from 0.5 to 30 ⁇ , preferably from 1 to 15 ⁇ , more preferably from 2.5 to 10 ⁇ and especially from 3 to 8.5 ⁇ .
  • Micronized edoxaban in accordance with the invention is usually obtainable by milling.
  • the milling can be performed in conventional milling apparatuses, such as in a ball mill, air jet mill, pin mill, classifier mill, cross beater mill, disk mill, mortar grinder or rotor mill.
  • An air jet mill is preferably used.
  • a ball mill is alternatively preferred.
  • the milling time is usually 0.5 minutes to 10 hours, preferably 2 minutes to 5 hours, more preferably 5 minutes to 3 hours.
  • the ratio of the Devalue to the Di 0 -value of the micronized edoxaban is between 1 : 1 and 20 : 1 , more preferably between 1.1 : 1 and 12 : 1 , even more preferably between 1.5 : 1 and 9 : 1 and especially between 2: 1 and 5 : 1. It appears that a small ratio of the Dgo-value to the Dio-value seems to be favourable for good distribution of the active agent within the composition and therefore assures that the above-mentioned objects are achieved.
  • the integral volume distribution of edoxaban can be monomodal or bimodal, preferably monomodal. That means that the integral volume distribution of edoxaban shows only one maximum in a graph or histogram representing a probability distribution of the particle sizes.
  • micronisation of an active pharmaceutical ingredient can entail disadvantages.
  • micronisation may result in an active agent with undesirably poor flowability.
  • the higher toxicity of the micronized active ingredient may make the handling more difficult and complicated with regard to health and safety.
  • the considerable enlargement of the surface area during micronisation may also cause the sensitivity of the active agent to oxidation to increase.
  • the composition of the present invention comprising micronized edoxaban and a C0 2 -forming agent does not suffer from said expected drawbacks, however, unexpectedly solves the above-mentioned objects.
  • the composition of the present invention can contain edoxaban in an amount of 5 to 120 mg, more preferably 10 to 90 mg, and especially 15 to 60 mg.
  • the composition of the present invention can contain edoxaban in a ratio of 0.1 to 80 wt.%, more preferably 1.5 to 60 wt.%, even more preferably 2.5 to 40 wt.% and especially 5.0 to 30 wt.%.
  • the dosage form of the present invention can contain the same amounts or ratios as mentioned above.
  • the C0 2 -formimg agent in the context of this invention can generally be a substance being capable of forming C0 2 when in contact with a preferably acidic aqueous solution, for example gastric juice.
  • the CC>2-formimg agent further can improve the dissolution of the active pharmaceutical ingredient.
  • the C0 2 -forming agent is capable of reducing the dissolution time of a pharmaceutical composition by 5 %, more preferably by 20 %, according to USP 31 -NF26 release method, using apparatus II (paddle), compared to the same pharmaceutical composition comprising no C0 2 -formimg agent.
  • a C0 2 -forming agent which can have a specific surface area of 0.01 to 45 m 2 /g, more preferably 0.05 to 25 m 2 /g, even more preferably 0.1 to 10 m 2 /g.
  • the specific surface area preferably is determined by gas adsorption according Ph. Eur., 6 th edition, Chapter 2.9.26. For this purpose an ASAP 2020 (Micromeritics) and an Outgassing' temperature of 40 °C is used.
  • the C0 2 -forming agent can preferably be an inorganic C0 2 -forming agent.
  • inorganic C0 2 -forming agents are inorganic salts containing anions, such as bicarbonate and carbonate and mixture thereof, wherein bicarbonate is most preferred.
  • examples of the corresponding cations of the above salts can be cations of alkali and alkaline metals, such as sodium, potassium, magnesium and calcium ion and mixtures thereof, especially sodium.
  • the C0 2 -forming agent preferably is an alkaline agent.
  • alkaline C0 2 -forming agent generally refers to substances, preferably salts, which, when dissolved in water, produce a pH level of more than 7.0.
  • the present inorganic C0 2 -forming agents can preferably be used in anhydrous form. It turned out that more superior properties of the composition and/or dosage form could be achieved by using a C0 2 -forming agent not being in the form of a hydrate.
  • Particularly preferred C0 2 -forming agents can be sodium bicarbonate or potassium bicarbonate. Especially preferred is sodium bicarbonate.
  • the weight ratio of edoxaban to Conforming agent is from 10 : 1 to 1 : 10, preferably from 5 : 1 to 1 : 5, more preferably from 3 : 1 to 1 : 3.
  • the C0 2 -forming agent can be present in an amount of 0.1 to 30 wt.%, preferably 1.0 to 25 wt.%, more preferably 3.0 to 20 wt.% and still more preferably 5.0 to 15 wt.%, based on the total weight of the composition or of the dosage form.
  • the C0 2 -forming agent can preferably be present from 0.01 to 35 wt.%, based on the total weight of the composition or of the dosage form.
  • the composition of the present invention can further comprise an organic acid, preferably an organic acid containing a hydroxy group. Further, preferably the organic acid has at least one pKa value from 1 to 7, more preferably from 2 to 6.
  • the organic acid preferably comprises 2 to 20, more preferably 3 to 10 carbon atoms.
  • suitable organic acids are tartaric acid, citric acid, lactic acid, malic acid and ascorbinic acid, wherein tartaric acid and citric acid are especially preferred, even more preferred is tartaric acid.
  • the organic acid can be present in an amount of 0.01 to 20 wt.%, preferably 0.1 to 15 wt.%, more preferably 1 .0 to 12 wt.% and still more preferably 2.0 to 10 wt.%, based on the total weight of the composition or of the dosage form.
  • the organic acid can be present in an amount of 1 to 40 wt.%, preferably 2 to 35 wt.%, more preferably 3 to 32 wt.% and still more preferably 5 to 30 wt.%, based on the total weight of the composition.
  • composition of the present invention can comprise one or more further excipients, preferably pharmaceutical excipients, preferably excipients as described in the European Pharmacopoeia (Ph. Eur.) and/or in the US Pharmacopoeia (USP).
  • excipients are binders, fillers, glidants, surfactants and/or lubricants.
  • the excipient can comprise a binder.
  • Binders usually are regarded as substances for ensuring that the composition can be formed with the required mechanical strength, preferably when compressing to a tablet.
  • the binder can be present in an amount of 0 to 30 wt.%, preferably 1 to 25 wt.%, more preferably 5 to 20 wt.% and still more preferably 7 to 15 wt.% based on the total weight of the composition or dosage form.
  • the binder can preferably be a polymer.
  • the polymer preferably has a glass transition temperature (Tg) of more than 18 °C, more preferably 30 °C to 150 °C, especially preferred 40 °C to 100 °C.
  • Tg glass transition temperature
  • the glass transition temperature is determined by means of dynamic differential scanning calorimetry (DSC).
  • DSC dynamic differential scanning calorimetry
  • a Mettler Toledo DSC 1 apparatus can be used. The work is performed at a heating rate of 1-20 °C/min., preferably 5- 15 °C/min., and at a cooling rate of 5-25 °C, preferably 10-20 °C/min.
  • composition and/or dosage form of the invention may, for example, comprise the following hydrophilic polymers as binder: polyvinyl pyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymers (such as Kollidon ® VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic ® , BASF), disaccharides, such as lactose, and mixtures of thereof.
  • hydrophilic polymers as binder: polyvinyl pyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymers (such as Kollidon ® VA64, BASF), polyalkylene glycol
  • Substances preferably used as binder can be polyvinyl pyrrolidone, preferably with a weight average molecular weight of 10,000 to 60,000 g/mol, especially 12,000 to 40,000 g/mol, a copolymer of vinyl pyrrolidone and vinyl acetate, especially with a weight average molecular weight of 40,000 to 70,000 g/mol and/or polyethylene glycol, especially with a weight average molecular weight of 2,000 to 10,000 g/mol.
  • Co-block polymers of polyethylene glycol and polypropylene glycol can preferably be used as binder, i.e. polyoxyethylene/polyoxypropylene block polymers.
  • These polymers preferably have a weight average molecular weight of 1 ,000 to 20,000 g/mol, more preferably 1 ,500 to 12,500 g/mol, especially 5,000 to 10,000 g/mol.
  • These block polymers are preferably obtained by condensation of propylene oxide with propylene glycol and subsequent condensation of the polymer formed with ethylene oxide. This means that the ethylene oxide content is preferably present as an "endblock".
  • the block polymers preferably have a weight ratio of propylene oxide to ethylene oxide of 50 : 50 to 95 : 5, more preferably of 70 : 30 to 90 : 10.
  • the block polymers preferably have a viscosity at 25 °C of 200 to 2,000 mPas, more preferably 500 to 1 ,500 mPas, especially 800 to 1 ,200 mPas.
  • the binder can be water-soluble. That means that the binder can have a water solubility at 25 °C from more than 5 mg/ml, preferably more than 20 mg/ml and especially more than 100 mg/ml.
  • the water solubility can be up to 500 mg/ml or even up to 1.000 mg/ml.
  • the water- solubility can be determined according to the column elution method of the Dangerous Substances Directive (67/548/EEC), Annex V, chapter A6.
  • cornstarch can preferably be used as binder.
  • the formulation of the invention can preferably contain fillers.
  • fillers generally refers to substances which serve, for example, to form the body of the tablet in the case of tablets with small amounts of active agent. This means that fillers "dilute" the active agents in order to produce an adequate dosage form mixture.
  • the normal purpose of fillers therefore, is to obtain a suitable dosage form size, preferably a suitable tablet size.
  • the filler can be water-soluble. That means that the binder can have a water solubility at 25 °C from more than 5 mg/ml, preferably more than 20 mg/ml and especially more than 100 mg/ml.
  • the water solubility can be up to 500 mg/ml or even up to 1.000 mg/ml.
  • Examples of preferred fillers are talcum, calcium phosphate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium sulphate, saccharose, lactose, monosaccharides, such as glucose, maltodextrin, dextrates, dextrin, hydrogenated vegetable oil, kaolin, sodium chloride, and/or potassium chloride.
  • the filler can be present in an amount of 0 to 50 wt.%, preferably 1 to 30 wt.%, more preferably 5 to 25 wt.% and still more preferably 7 to 20 wt.%, based on the total weight of the composition.
  • a glidant is disperse or colloidal silica (for example Aerosil ® ).
  • Glidants may be present in an amount of 0 to 5 wt.%, preferably 1 to 4 wt.% of the total weight of the composition or dosage form.
  • the glidant can be present in an amount of 0.05 to 3 wt.%, preferably 0.1 to 2.5 wt.% of the total weight of the composition.
  • Surfactants can be regarded as substances lowering the interfacial tension between two phases, thus enabling or supporting the formation of dispersions or working as a solubilizer.
  • surfactants are alkylsufates, preferably containing a Ci 0 to C 18 alkyl group (e.g. sodium lauryl sulfate), alkyltrimethylammoniumsalts, alcohol ethoxylates and the like. Further, polyoxyethylene derivatives of sorbitan monolaurate (marketed as "Tween”) are preferred. Sodium lauryl sulfate is particularly preferred.
  • Surfactants can be used in an amount of 0.05 to 3.0% by weight, preferably of 0.1 to 2.5% by weight and most preferably of 0.2 to 2.0% by weight, based on the total weight of the composition. It has been found that a combination of C0 2 -forming agent and surfactant is particularly advantageous in solving the above-mentioned problems.
  • the weight ratio of C0 2 -forming agent to surfactant is from 50 : 1 to 2 : 1 , preferably from 20 : 1 to 5 : 1 , more preferably from 15 : 1 to 7 : 1.
  • Lubricants may be used.
  • Lubricants are generally used in order to reduce sliding friction. In particular, the intention is to reduce the sliding friction found during tablet pressing between the punch moving up and down in the die and the die wall, on the one hand, and between the edge of the tablet and the die wall, on the other hand.
  • Suitable lubricants are, for example, stearic acid, adipic acid, sodium stearyl fumarate and/or magnesium stearate.
  • Sodium stearyl fumarate (PRUV ® ) is particularly preferred.
  • Lubricants are generally used in an amount of 0.1 to 3 % by weight, based on the total weight of the composition. In an alternatively preferred embodiment lubricants can be used in an amount of 0.05 to 4% by weight, preferably of 0.3 to 3% by weight, based on the total weight of the composition. It lies in the nature of pharmaceutical excipients that they sometimes can perform more than one function in a pharmaceutical formulation. Therefore, some pharmaceutically acceptable ingredients may function as pharmaceutical excipient as well as C0 2 -forming agent, i.e. the fact that an ingredient is used e.g. as a filler, does not mean that it cannot also be acting as a C0 2 -forming agent. For example, magnesium carbonate in a present composition may act both as a filler and as a C0 2 -forming agent.
  • the fiction will therefore preferably apply that a substance which is used as a particular excipient is not simultaneously also used as a further pharmaceutical excipient.
  • a substance which is used as a particular excipient is not simultaneously also used as a further pharmaceutical excipient.
  • lactose - if used as a binder- is not additionally used as filler (even though lactose can be used as filler).
  • the present composition comprises edoxaban, Conforming agent, organic acid, binder, filler, glidant, surfactant and/or lubricant.
  • the composition of the present invention comprises: 0.1 to 80 wt.%, more preferably 1.5 to 60 wt.%, even more preferably 2.5 to 40 wt.% and especially 5.0 to 30 wt.% edoxaban, preferably edoxaban tosylate; 0.1 to 35 wt.%, preferably 1.0 to 30 wt.%, more preferably 3.0 to 20 wt.% and still more preferably 5.0 to 15 wt.%, C0 2 -forming agent;
  • wt.% preferably 1 to 25 wt.%, more preferably 5 to 20 wt.% and still more preferably 7 to 15 wt.% binder;
  • wt.% preferably 1 to 30 wt.%, more preferably 5 to 25 wt.% and still more preferably 7 to 20 wt.% filler;
  • glidant preferably silica
  • lubricant preferably 0 to 3 wt.%, preferably 0.1 to 2.5 wt.% glidant, preferably silica; 0 to 4% by weight, preferably 0.3 to 3% by weight lubricant,
  • the composition of the present invention can be used as intermediate or as final dosage form.
  • the composition of the present invention is used as intermediate, which is preferably further processed into a dosage form, more preferably into a solid dosage form, still more preferably into a solid oral dosage form.
  • the processing into a dosage form can be achieved by means of suitable methods, such as filling into sachets or capsules or by compressing into tablets.
  • the composition can be granulated. Direct compression is preferred.
  • composition of the invention can be employed to prepare a dosage form, preferably an oral dosage form, more preferably a solid oral dosage form, in particular a capsule or tablet.
  • the dosage form can be a tablet.
  • the tablet of the invention preferably can have a hardness of 25 o to 250 N, particularly preferably of 30 to 180 N or 40 to 150 N.
  • the hardness is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.8.
  • the tablet of the invention preferably can have a friability of less than 3 %, more preferably less than 2 %, in particular 0.1 to 1.2 %.
  • the friability is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.7.
  • the tablet of the invention preferably can have a "content uniformity" of 93 to 107 %, more preferably 95 to 105 %, still more preferably 98 to 102 %, particularly 99 to 101 % of the average content.
  • the "content uniformity” is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.6. The above details regarding hardness, friability and content uniformity preferably relate to the non-film-coated tablet.
  • the composition and/ or the dosage form according to the invention provides an immediate release ("IR") of edoxaban.
  • IR immediate release
  • the release profile of the dosage forms of the invention according to USP method (paddle, 900 ml, 0.1 n HCl, 75 rpm, 37 °C) after 10 minutes usually indicates a content release of at least 75 %, preferably at least 85 %, especially at least 90 %.
  • the release can be up to 95 %, preferably up to 100 %.
  • the dosage form of the invention tablets may be a tablet, which can be swallowed unchewed (non-film-coated or preferably film-coated).
  • the tablet of the present application can be film-coated.
  • methods known in the art for film-coating a tablet may be employed.
  • film-coatings can be prepared by using cellulose derivatives, poly(meth)acrylate, polyvinyl pyrrolidone, polyvinyl acetate phthalate, and/or shellac or natural rubbers such as carrageenan.
  • the film-coating can be a film- coating essentially without affecting the release of the active agent.
  • Preferred examples of film-coatings, which do not affect the release of the active ingredient can be those including poly(meth)acrylate, methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyvinyl pyrrolidone (PVP) and mixtures thereof. These polymers can have an average molecular weight of 10,000 to 150,000 g/mol.
  • a further subject of the invention is a method for preparing the dosage form of the present invention comprising the steps of (al) mixing edoxaban, C0 2 -forming agent and optionally one ore more pharmaceutical excipient(s),
  • step (a3) processing the mixture resulting from step (al) or the granulates from (a2) into a dosage form
  • step (al ) can be characterized by mixing edoxaban, preferably micronized edoxaban, a C0 2 -forming agent and optionally one or more pharmaceutical excipient(s) as outlined above.
  • the mixing (al) can be carried out with conventional mixing devices. In order to ensure an even distribution, mixing in intensive mixers is preferred. Suitable mixing devices can preferably be compulsory mixers or free fall mixer, for example a Turbula ® T 10B (Bachofen AG, Switzerland). Mixing can be carried out, for example, for 1 minute to 1 hour, preferably for 5 to 30 minutes.
  • mixing (al ) can be conducted such that the edoxaban, preferably the micronized edoxaban, can be mixed with a first part of the C0 2 - forming agent and/or excipient(s) in a mixing device, for example in a high shear or tumbler mixer.
  • a second part of the C0 2 -forming agent and/or excipient(s) can be added, which may be followed by a second mixing step.
  • This procedure can be repeated until the last part of the C0 2 -forming agent and/or excipient(s) is used, preferably used one to five times.
  • This kind of mixing can assure an even distribution of the active agent and provides a mass for further processing in step (a2) or step (a3), for example for a granulation or tableting process.
  • step (a2) the mixture from step (al) can be optionally granulated.
  • "Granulating” is generally understood to mean the formation of relatively coarse or granular aggregate material as a powder by assembling and/or aggregating finer powder particles (agglomerate formation, or build-up granulation) and/or the formation of finer granules by breaking up coarser aggregates (disintegration, or break-down granulation).
  • Granulation can conventionally mean wet or dry granulation. Dry granulation, which is preferred, is generally carried out by using pressure or temperature.
  • optionally granulating the mixture from step (al) can be performed, for example, by "slugging", using a large heavy-duty rotary press and breaking up the slugs to granulates with a hammer mill or by roller compaction, using for example roller compactors by Powtec or Alexanderwerk. The granulates are then optionally screened.
  • step (a3) the mixture resulting from step (al) or optionally the granulates from step (a2) can be further processed into a dosage form.
  • said mixture or said granulates can, for example, be filled into sachets or capsules.
  • step (a3) can include compressing the mixture resulting from step (al) or optionally the granulates from step (a2) and optionally further excipient(s), such as lubricant, into tablets.
  • the compression of the mixture of step (al) can preferably be a direct compression.
  • This direct compression step can preferably be carried out on a rotary press, for example on a Fette ® 102i (Fette GmbH, Germany) or a Riva ® piccola (Riva, Argentina). If a rotary press is applied, the main compaction force can range from 1 to 50 kN, preferably from 2 to 40 kN, more preferably form 3 to 30 kN.
  • the granulates from step (a2) can be compressed into tablets. Further, the granulates could be filled into capsules or other dosage forms like stick-packs or sachets.
  • the tablet can optionally be film-coated.
  • Film-coating is preferred for tablets for peroral use.
  • the composition of the present invention is in form of a peroral tablet or filled into a capsule.
  • the composition of the present invention is in form of an effervescent tablet to be dissolved in a liquid.
  • the composition of the present invention can be an oral dosage form, wherein the composition is filled into suitable devices like sachets or stick-packs.
  • the dosage form may be administered in a single daily dose or in divided doses of two to six times a day.
  • the dosage form of edoxaban may be administered less frequently then once daily, e.g. every second, third, or fourth day.
  • the dosage form of the present invention is administered once or twice daily. It has been unexpectedly found that the dosage form of the present invention can be administered independently from the meals of the patient, i.e. the dosage forms of the present invention are suitable to be administered before, during or after the meals.
  • the dosage forms of the invention are administered daily at a dose of from about 5 to about 120 mg/d, preferably 10 to 90 mg/d, more preferably 15 to 60 mg/d.
  • the dosage form of the present invention preferably shows superior dissolution and absorption characteristics upon administration, leading to desirable plasma values like desirable AUC (area under the curve from 0 to 48 hours after oral administration), C max and T ma x values.
  • administration of the dosage form of the present invention results in a T max value of 0.5 to 3 hours, more preferably of 0.75 to 1.5 hours.
  • administration of the dosage form of the present invention (in a strength of 30 mg calculated for the free base of Edoxaban) results in a Cmax value of 100 to 300 ng/ l, more preferably 150 to 250 ng/ml.
  • administration of the dosage form of the present invention results in a C ma value of 150 to 500 ng/ml, more preferably 200 to 350 ng/ml.
  • administration of the dosage form of the present invention results in a strength of 30 mg calculated for the free base of Edoxaban results in a AUC value of 500 to 3000 ng h/ml, more preferably 750 to 1500 ng h/ml.
  • the plasma values are an average of ten single measurement values, determined upon administration to 10 male humans having a body weight of about 75 kg.
  • the dosage forms of the present invention are used in the management (e.g. in the prevention or treatment) of thrombotic disorders.
  • a further subject of the invention is a dosage form according to the invention for managing thrombotic disorders.
  • patients having at least one of the following risks, can be advantageously treated: age 66 years or older, elevated cardiac biomarkers, cerebrovascular diseases, peripheral vascular disease, non- revascularizable multivessel coronary artery disease, renal insufficiency and diabetes mellitus.
  • the dosage form according to the invention can be used for preventing or treating thrombotic disorders, wherein the dosage form is administered in a patient suffering from diabetes mellitus.
  • a further subject of the invention is the use of a C0 2 -forming agent and/or an inorganic filler for producing an antithrombotic-drug-containing dosage form, preferably edoxaban-containing dosage form which is free of sugar alcohol.

Abstract

The invention relates to compositions and dosage forms containing edoxaban and a C02-forming agent, preferably for immediate release. Further the invention relates to the method for preparing said dosage forms and their use in the treatment of thrombotic diseases.

Description

Composition comprising Edoxaban
Background The invention relates to compositions containing edoxaban and a C02-forming agent, preferably for immediate release. The invention also relates to methods of preparing dosage forms containing said compositions.
Edoxaban is reported to be a member of the so-called "Xaban-group" and as such to be a low molecular inhibitor of the enzyme factor Xa, participating in the blood coagulation system. Therefore, edoxaban is classified as an antithrombotic drug and its possible medical indications are reported to be treatment of thrombosis and thrombosis prophylaxis after orthopaedic operations, such as total hip replacement, as well as for stroke prevention in patients with atrial fibrillation, the prophylaxis of the acute coronary syndrome and the prophylaxis after thrombosis and pulmonary embolism.
The IUPAC name for edoxaban is N'-(5-chloropyridin-2-yl)-N-[(15,2^,4S)-4- (dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[l ,3]thiazolo[5,4-c]pyridine-2- carbonyl)amino]cyclohexyl]oxamide. The chemical structure of edoxaban is shown in the formula (1) below:
Figure imgf000002_0001
formula ( 1 ) While Edoxaban is reported to be soluble in strongly acidic aqueous solutions, its solubility is considered to be very low in neutral or alkaline aqueous media. EP 2 140 867 A 1 claims an edoxaban-containing pharmaceutical composition comprising a water-swelling additive and/or a sugar alcohol. Further, it is alleged that compositions comprising lactose or cornstarch do not have good dissolution properties. The claimed pharmaceutical compositions in EP 2 140 867 Al are considered to show good dissolution properties in a neutral aqueous medium as well. Tablets comprising said composition were produced by wet granulation. However, it turned out that prior art pharmaceutical formulations comprising edoxaban being suitable for oral administration are still improvable with regards to dissolution rate and bioavailability. Further, stability and content uniformity of the known formulations could be improved. Further, due to the intolerance of many people to sugar alcohol(s), such as sorbitol, the use of sugar alcohol(s) should be avoided.
Hence, it was an object of the present invention to overcome the above-mentioned disadvantages. It was an object of the present invention to provide superior content uniformity of the active agent, even in combination with direct compression.
It was a further object of the invention to provide a dosage form being free of sugar alcohol(s).
It was a further object of the invention to provide the active agent in a formulation, which possesses superior dissolution rates and bioavailability as well as superior storage stability at the same time. The advantageous properties should be achieved even if (cheap) excipients like saccharose and cornstarch are used, which are described as disadvantageous in the prior art. Expensive processes like melt granulation should be avoided. Finally, it was the intention to provide the active agent in a form which possesses good flowability and enables easy processing.
Summary of the Invention
According to the present invention, the above objectives are achieved by a composition, in particular a pharmaceutical composition, containing edoxaban and a C02-forming agent. The composition can be further processed into a dosage form, preferably by direct compression.
It was found that the composition and or dosage form of the present invention can be free of sugar alcohols and has superior dissolution rates and superior permeability, resulting in an excellent bioavailability of the active pharmaceutical ingredient. Further, even when wet granulation was avoided, a superior content uniformity of the drug was achieved, which ensured that the appropriate dose was applied to the patient. It was further found that the composition/dosage form of the present invention was very stable over a prolonged period of time.
Hence, a subject of the present invention is a composition containing edoxaban and a C02-forming agent.
Another subject of the invention is a method for preparing a composition and/or dosage form containing edoxaban and a C02-forming agent comprising the steps of mixing edoxaban, C02-forming agent and optionally one or more pharmaceutical excipient(s),
(a2) optionally granulating the mixture from step (al), and
(a3) processing the mixture resulting from step (al) or the granulates from (a2) into a dosage form, and
(a4) optionally film-coating the dosage form. Finally, another subject of the invention is the use of a Conforming agent and/or inorganic filler for producing an edoxaban-containing dosage form which is free of sugar alcohol and/or water-swelling excipients. Detailed Description of the Invention
In the context of this invention, the term "edoxaban" comprises N'-(5- chloropyridin-2-yl)-N-[( 1552i?,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7- dihydro-4H-[l ,3]thiazolo-[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide in accordance with formula (1 ) above. In addition, the term "edoxaban" comprises all the pharmaceutically acceptable salts, hydrates and/or solvates thereof, for example edoxaban tosylate. Preferably, edoxaban is used in form of the free base. Alternatively, edoxaban is used in the form of the tosylate monohydrate salt. Within the present application, ratios or amounts of edoxaban generally refer to the ratio or amount of edoxaban in form of the free base.
In a particularly preferred embodiment the composition or the dosage form of the present invention can comprise edoxaban as the sole pharmaceutical active agent. In an alternative embodiment the composition or the dosage form of the present invention can comprise edoxaban in combination with further pharmaceutical active agent(s).
For all the embodiments of this invention, the term "edoxaban" preferably means edoxaban in crystalline form, i.e. preferably more than 90 % by weight of the edoxaban used is in crystalline form, especially preferred 100 %.
In a preferred embodiment of the invention the average particle size (D50-value) of edoxaban can be from 0. 1 to 150 μιη, preferably from 0.15 to 100 μηι, more preferably from 0.2 to 75 μηι.
In a further embodiment of the invention the edoxaban can be micronized edoxaban. The expression "micronized edoxaban" is used in the context of this invention to designate particulate edoxaban, which generally has an average particle diameter (D50-value) of 0.1 to 20 μπι, preferably 0.3 to 10 μπι, more preferably 0.5 to 5 μιη and especially 1.0 to 4.0 μτη.
The expression "average particle diameter" relates in the context of this invention to the D50value of the volume-average particle diameter determined by means of laser diffractometry. In particular, a Malvern Instruments Mastersizer 2000 was used to determine the diameter (wet measurement, 2,000 rpm, ultrasonic 60 sec, preferably shading 4 to 13 %, preferably dispersion in liquid paraffin, evaluated according to the Fraunhofer method). The average particle diameter, which is also referred to as the D5o-value of the integral volume distribution, is defined in the context of this invention as the particle diameter, at which 50 % by volume of the particles have a smaller diameter than the diameter which corresponds to the D 0 value. Similarly, 50 % by volume of the particles then have a larger diameter than the D50 value.
Analogously, the Di0-value of the integral volume distribution is defined as the particle diameter at which 10 % by volume of the particles have a smaller diameter than the diameter which corresponds to the Di0-value. In a preferred embodiment the Dio-value of the integral volume distribution is from 0.01 to 7 μπι, preferably from 0.05 to 5 μπι, more preferably from 0.1 to 3.5 μπι and especially from 0.5 to 1.5 μπι. Analogously, the Dgo-value of the integral volume distribution is defined as the particle diameter at which 90 % by volume of the particles have a smaller diameter than the diameter which corresponds to the D90-value. In a preferred embodiment the Devalue of the integral volume distribution is from 0.5 to 30 μηι, preferably from 1 to 15 μπι, more preferably from 2.5 to 10 μηι and especially from 3 to 8.5 μηι. Micronized edoxaban in accordance with the invention is usually obtainable by milling.
The milling can be performed in conventional milling apparatuses, such as in a ball mill, air jet mill, pin mill, classifier mill, cross beater mill, disk mill, mortar grinder or rotor mill. An air jet mill is preferably used. A ball mill is alternatively preferred.
The milling time is usually 0.5 minutes to 10 hours, preferably 2 minutes to 5 hours, more preferably 5 minutes to 3 hours.
In a preferred embodiment the ratio of the Devalue to the Di0-value of the micronized edoxaban is between 1 : 1 and 20 : 1 , more preferably between 1.1 : 1 and 12 : 1 , even more preferably between 1.5 : 1 and 9 : 1 and especially between 2: 1 and 5 : 1. It appears that a small ratio of the Dgo-value to the Dio-value seems to be favourable for good distribution of the active agent within the composition and therefore assures that the above-mentioned objects are achieved.
In a preferred embodiment the integral volume distribution of edoxaban can be monomodal or bimodal, preferably monomodal. That means that the integral volume distribution of edoxaban shows only one maximum in a graph or histogram representing a probability distribution of the particle sizes.
Usually, micronisation of an active pharmaceutical ingredient (API) can entail disadvantages. For example, micronisation may result in an active agent with undesirably poor flowability. In addition, the higher toxicity of the micronized active ingredient may make the handling more difficult and complicated with regard to health and safety. The considerable enlargement of the surface area during micronisation may also cause the sensitivity of the active agent to oxidation to increase. However, in the present invention it has surprisingly been found that the composition of the present invention comprising micronized edoxaban and a C02-forming agent does not suffer from said expected drawbacks, however, unexpectedly solves the above-mentioned objects.
In a preferred embodiment the composition of the present invention can contain edoxaban in an amount of 5 to 120 mg, more preferably 10 to 90 mg, and especially 15 to 60 mg. In a further preferred embodiment the composition of the present invention can contain edoxaban in a ratio of 0.1 to 80 wt.%, more preferably 1.5 to 60 wt.%, even more preferably 2.5 to 40 wt.% and especially 5.0 to 30 wt.%. Furthermore, also the dosage form of the present invention can contain the same amounts or ratios as mentioned above.
The C02-formimg agent in the context of this invention can generally be a substance being capable of forming C02 when in contact with a preferably acidic aqueous solution, for example gastric juice. The CC>2-formimg agent further can improve the dissolution of the active pharmaceutical ingredient. Preferably, the C02-forming agent is capable of reducing the dissolution time of a pharmaceutical composition by 5 %, more preferably by 20 %, according to USP 31 -NF26 release method, using apparatus II (paddle), compared to the same pharmaceutical composition comprising no C02-formimg agent.
Furthermore, a C02-forming agent is preferred which can have a specific surface area of 0.01 to 45 m2/g, more preferably 0.05 to 25 m2/g, even more preferably 0.1 to 10 m2/g. The specific surface area preferably is determined by gas adsorption according Ph. Eur., 6th edition, Chapter 2.9.26. For this purpose an ASAP 2020 (Micromeritics) and an Outgassing' temperature of 40 °C is used.
In a preferred embodiment the C02-forming agent can preferably be an inorganic C02-forming agent. Examples of especially preferred inorganic C02-forming agents are inorganic salts containing anions, such as bicarbonate and carbonate and mixture thereof, wherein bicarbonate is most preferred. Examples of the corresponding cations of the above salts can be cations of alkali and alkaline metals, such as sodium, potassium, magnesium and calcium ion and mixtures thereof, especially sodium. Further, the C02-forming agent preferably is an alkaline agent. The term alkaline C02-forming agent generally refers to substances, preferably salts, which, when dissolved in water, produce a pH level of more than 7.0.
The present inorganic C02-forming agents can preferably be used in anhydrous form. It turned out that more superior properties of the composition and/or dosage form could be achieved by using a C02-forming agent not being in the form of a hydrate.
Particularly preferred C02-forming agents can be sodium bicarbonate or potassium bicarbonate. Especially preferred is sodium bicarbonate.
In a preferred embodiment of the present composition the weight ratio of edoxaban to Conforming agent is from 10 : 1 to 1 : 10, preferably from 5 : 1 to 1 : 5, more preferably from 3 : 1 to 1 : 3.
The C02-forming agent can be present in an amount of 0.1 to 30 wt.%, preferably 1.0 to 25 wt.%, more preferably 3.0 to 20 wt.% and still more preferably 5.0 to 15 wt.%, based on the total weight of the composition or of the dosage form. In an alternative embodiment the C02-forming agent can preferably be present from 0.01 to 35 wt.%, based on the total weight of the composition or of the dosage form. According to another preferred embodiment the composition of the present invention can further comprise an organic acid, preferably an organic acid containing a hydroxy group. Further, preferably the organic acid has at least one pKa value from 1 to 7, more preferably from 2 to 6. Further, the organic acid preferably comprises 2 to 20, more preferably 3 to 10 carbon atoms. Examples of suitable organic acids are tartaric acid, citric acid, lactic acid, malic acid and ascorbinic acid, wherein tartaric acid and citric acid are especially preferred, even more preferred is tartaric acid. The organic acid can be present in an amount of 0.01 to 20 wt.%, preferably 0.1 to 15 wt.%, more preferably 1 .0 to 12 wt.% and still more preferably 2.0 to 10 wt.%, based on the total weight of the composition or of the dosage form. In an alternatively preferred embodiment the organic acid can be present in an amount of 1 to 40 wt.%, preferably 2 to 35 wt.%, more preferably 3 to 32 wt.% and still more preferably 5 to 30 wt.%, based on the total weight of the composition.
In a further preferred embodiment the composition of the present invention can comprise one or more further excipients, preferably pharmaceutical excipients, preferably excipients as described in the European Pharmacopoeia (Ph. Eur.) and/or in the US Pharmacopoeia (USP). In this regard it is noted that all explanations given above for the composition also apply to the dosage form of the present invention. Examples of excipients used are binders, fillers, glidants, surfactants and/or lubricants.
In a preferred embodiment of the composition of the present invention the excipient can comprise a binder. Binders usually are regarded as substances for ensuring that the composition can be formed with the required mechanical strength, preferably when compressing to a tablet.
The binder can be present in an amount of 0 to 30 wt.%, preferably 1 to 25 wt.%, more preferably 5 to 20 wt.% and still more preferably 7 to 15 wt.% based on the total weight of the composition or dosage form.
The binder can preferably be a polymer. The polymer preferably has a glass transition temperature (Tg) of more than 18 °C, more preferably 30 °C to 150 °C, especially preferred 40 °C to 100 °C. In the context of this invention the glass transition temperature is determined by means of dynamic differential scanning calorimetry (DSC). For this purpose a Mettler Toledo DSC 1 apparatus can be used. The work is performed at a heating rate of 1-20 °C/min., preferably 5- 15 °C/min., and at a cooling rate of 5-25 °C, preferably 10-20 °C/min.
The composition and/or dosage form of the invention may, for example, comprise the following hydrophilic polymers as binder: polyvinyl pyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymers (such as Kollidon® VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic®, BASF), disaccharides, such as lactose, and mixtures of thereof.
Substances preferably used as binder can be polyvinyl pyrrolidone, preferably with a weight average molecular weight of 10,000 to 60,000 g/mol, especially 12,000 to 40,000 g/mol, a copolymer of vinyl pyrrolidone and vinyl acetate, especially with a weight average molecular weight of 40,000 to 70,000 g/mol and/or polyethylene glycol, especially with a weight average molecular weight of 2,000 to 10,000 g/mol. Co-block polymers of polyethylene glycol and polypropylene glycol can preferably be used as binder, i.e. polyoxyethylene/polyoxypropylene block polymers. These polymers preferably have a weight average molecular weight of 1 ,000 to 20,000 g/mol, more preferably 1 ,500 to 12,500 g/mol, especially 5,000 to 10,000 g/mol. These block polymers are preferably obtained by condensation of propylene oxide with propylene glycol and subsequent condensation of the polymer formed with ethylene oxide. This means that the ethylene oxide content is preferably present as an "endblock". The block polymers preferably have a weight ratio of propylene oxide to ethylene oxide of 50 : 50 to 95 : 5, more preferably of 70 : 30 to 90 : 10. The block polymers preferably have a viscosity at 25 °C of 200 to 2,000 mPas, more preferably 500 to 1 ,500 mPas, especially 800 to 1 ,200 mPas. In a preferred embodiment of the invention, the binder can be water-soluble. That means that the binder can have a water solubility at 25 °C from more than 5 mg/ml, preferably more than 20 mg/ml and especially more than 100 mg/ml. The water solubility can be up to 500 mg/ml or even up to 1.000 mg/ml. The water- solubility can be determined according to the column elution method of the Dangerous Substances Directive (67/548/EEC), Annex V, chapter A6.
In an alternative embodiment cornstarch can preferably be used as binder. The formulation of the invention can preferably contain fillers. The term "fillers" generally refers to substances which serve, for example, to form the body of the tablet in the case of tablets with small amounts of active agent. This means that fillers "dilute" the active agents in order to produce an adequate dosage form mixture. The normal purpose of fillers, therefore, is to obtain a suitable dosage form size, preferably a suitable tablet size.
In a preferred embodiment of the invention, the filler can be water-soluble. That means that the binder can have a water solubility at 25 °C from more than 5 mg/ml, preferably more than 20 mg/ml and especially more than 100 mg/ml. The water solubility can be up to 500 mg/ml or even up to 1.000 mg/ml.
Examples of preferred fillers are talcum, calcium phosphate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium sulphate, saccharose, lactose, monosaccharides, such as glucose, maltodextrin, dextrates, dextrin, hydrogenated vegetable oil, kaolin, sodium chloride, and/or potassium chloride.
The filler can be present in an amount of 0 to 50 wt.%, preferably 1 to 30 wt.%, more preferably 5 to 25 wt.% and still more preferably 7 to 20 wt.%, based on the total weight of the composition.
An example of a glidant is disperse or colloidal silica (for example Aerosil®). Glidants may be present in an amount of 0 to 5 wt.%, preferably 1 to 4 wt.% of the total weight of the composition or dosage form. In an alternatively preferred embodiment the glidant can be present in an amount of 0.05 to 3 wt.%, preferably 0.1 to 2.5 wt.% of the total weight of the composition. Surfactants can be regarded as substances lowering the interfacial tension between two phases, thus enabling or supporting the formation of dispersions or working as a solubilizer. Examples of surfactants are alkylsufates, preferably containing a Ci0 to C18 alkyl group (e.g. sodium lauryl sulfate), alkyltrimethylammoniumsalts, alcohol ethoxylates and the like. Further, polyoxyethylene derivatives of sorbitan monolaurate (marketed as "Tween") are preferred. Sodium lauryl sulfate is particularly preferred.
Surfactants can be used in an amount of 0.05 to 3.0% by weight, preferably of 0.1 to 2.5% by weight and most preferably of 0.2 to 2.0% by weight, based on the total weight of the composition. It has been found that a combination of C02-forming agent and surfactant is particularly advantageous in solving the above-mentioned problems. In a preferred embodiment the weight ratio of C02-forming agent to surfactant is from 50 : 1 to 2 : 1 , preferably from 20 : 1 to 5 : 1 , more preferably from 15 : 1 to 7 : 1.
In addition, lubricants may be used. Lubricants are generally used in order to reduce sliding friction. In particular, the intention is to reduce the sliding friction found during tablet pressing between the punch moving up and down in the die and the die wall, on the one hand, and between the edge of the tablet and the die wall, on the other hand. Suitable lubricants are, for example, stearic acid, adipic acid, sodium stearyl fumarate and/or magnesium stearate. Sodium stearyl fumarate (PRUV®) is particularly preferred.
Lubricants are generally used in an amount of 0.1 to 3 % by weight, based on the total weight of the composition. In an alternatively preferred embodiment lubricants can be used in an amount of 0.05 to 4% by weight, preferably of 0.3 to 3% by weight, based on the total weight of the composition. It lies in the nature of pharmaceutical excipients that they sometimes can perform more than one function in a pharmaceutical formulation. Therefore, some pharmaceutically acceptable ingredients may function as pharmaceutical excipient as well as C02-forming agent, i.e. the fact that an ingredient is used e.g. as a filler, does not mean that it cannot also be acting as a C02-forming agent. For example, magnesium carbonate in a present composition may act both as a filler and as a C02-forming agent.
However, in order to provide an unambiguous delimitation in the context of this invention, the fiction will therefore preferably apply that a substance which is used as a particular excipient is not simultaneously also used as a further pharmaceutical excipient. For example, lactose - if used as a binder- is not additionally used as filler (even though lactose can be used as filler). In a preferred embodiment the present composition comprises edoxaban, Conforming agent, organic acid, binder, filler, glidant, surfactant and/or lubricant.
Preferably, the composition of the present invention comprises: 0.1 to 80 wt.%, more preferably 1.5 to 60 wt.%, even more preferably 2.5 to 40 wt.% and especially 5.0 to 30 wt.% edoxaban, preferably edoxaban tosylate; 0.1 to 35 wt.%, preferably 1.0 to 30 wt.%, more preferably 3.0 to 20 wt.% and still more preferably 5.0 to 15 wt.%, C02-forming agent;
0 to 30 wt.%, preferably 1 to 25 wt.%, more preferably 5 to 20 wt.% and still more preferably 7 to 15 wt.% binder;
0 to 50 wt.%, preferably 1 to 30 wt.%, more preferably 5 to 25 wt.% and still more preferably 7 to 20 wt.% filler;
0 to 40 wt.%, preferably 2 to 35 wt.%, more preferably 3 to 32 wt.% and still more preferably 5 to 30 wt.% organic acid;
0 to 3.0% by weight, preferably 0.1 to 2.5% by weight and still more preferably 0.2 to 2.0 % surfactant, preferably sodium lauryl sulfate;
0 to 3 wt.%, preferably 0.1 to 2.5 wt.% glidant, preferably silica; 0 to 4% by weight, preferably 0.3 to 3% by weight lubricant,
based on the total weight of the composition.
Generally, the composition of the present invention can be used as intermediate or as final dosage form. Preferably, the composition of the present invention is used as intermediate, which is preferably further processed into a dosage form, more preferably into a solid dosage form, still more preferably into a solid oral dosage form. The processing into a dosage form can be achieved by means of suitable methods, such as filling into sachets or capsules or by compressing into tablets. Optionally, before the filling or compression step the composition can be granulated. Direct compression is preferred.
Therefore, the composition of the invention can be employed to prepare a dosage form, preferably an oral dosage form, more preferably a solid oral dosage form, in particular a capsule or tablet.
In a preferred embodiment of the invention the dosage form can be a tablet.
The tablet of the invention preferably can have a hardness of 25 o to 250 N, particularly preferably of 30 to 180 N or 40 to 150 N. The hardness is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.8.
In addition, the tablet of the invention preferably can have a friability of less than 3 %, more preferably less than 2 %, in particular 0.1 to 1.2 %. The friability is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.7.
Further, the tablet of the invention preferably can have a "content uniformity" of 93 to 107 %, more preferably 95 to 105 %, still more preferably 98 to 102 %, particularly 99 to 101 % of the average content. The "content uniformity" is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.6. The above details regarding hardness, friability and content uniformity preferably relate to the non-film-coated tablet.
In a preferred embodiment the composition and/ or the dosage form according to the invention provides an immediate release ("IR") of edoxaban. This means that the release profile of the dosage forms of the invention according to USP method (paddle, 900 ml, 0.1 n HCl, 75 rpm, 37 °C) after 10 minutes usually indicates a content release of at least 75 %, preferably at least 85 %, especially at least 90 %. The release can be up to 95 %, preferably up to 100 %.
The dosage form of the invention tablets may be a tablet, which can be swallowed unchewed (non-film-coated or preferably film-coated).
In a preferred embodiment, the tablet of the present application can be film-coated. For this purpose, methods known in the art for film-coating a tablet may be employed.
Generally, film-coatings can be prepared by using cellulose derivatives, poly(meth)acrylate, polyvinyl pyrrolidone, polyvinyl acetate phthalate, and/or shellac or natural rubbers such as carrageenan.
In a preferred embodiment of the present invention the film-coating can be a film- coating essentially without affecting the release of the active agent. Preferred examples of film-coatings, which do not affect the release of the active ingredient, can be those including poly(meth)acrylate, methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyvinyl pyrrolidone (PVP) and mixtures thereof. These polymers can have an average molecular weight of 10,000 to 150,000 g/mol.
A further subject of the invention is a method for preparing the dosage form of the present invention comprising the steps of (al) mixing edoxaban, C02-forming agent and optionally one ore more pharmaceutical excipient(s),
(a2) optionally granulating the mixture from (al),
(a3) processing the mixture resulting from step (al) or the granulates from (a2) into a dosage form, and
(a4) optionally film-coating the dosage from.
In a preferred embodiment, step (al ) can be characterized by mixing edoxaban, preferably micronized edoxaban, a C02-forming agent and optionally one or more pharmaceutical excipient(s) as outlined above.
The mixing (al) can be carried out with conventional mixing devices. In order to ensure an even distribution, mixing in intensive mixers is preferred. Suitable mixing devices can preferably be compulsory mixers or free fall mixer, for example a Turbula® T 10B (Bachofen AG, Switzerland). Mixing can be carried out, for example, for 1 minute to 1 hour, preferably for 5 to 30 minutes.
In preferred embodiment, mixing (al ) can be conducted such that the edoxaban, preferably the micronized edoxaban, can be mixed with a first part of the C02- forming agent and/or excipient(s) in a mixing device, for example in a high shear or tumbler mixer. After this first mixing step a second part of the C02-forming agent and/or excipient(s) can be added, which may be followed by a second mixing step. This procedure can be repeated until the last part of the C02-forming agent and/or excipient(s) is used, preferably used one to five times. This kind of mixing can assure an even distribution of the active agent and provides a mass for further processing in step (a2) or step (a3), for example for a granulation or tableting process.
In step (a2) the mixture from step (al) can be optionally granulated. "Granulating" is generally understood to mean the formation of relatively coarse or granular aggregate material as a powder by assembling and/or aggregating finer powder particles (agglomerate formation, or build-up granulation) and/or the formation of finer granules by breaking up coarser aggregates (disintegration, or break-down granulation).
Granulation can conventionally mean wet or dry granulation. Dry granulation, which is preferred, is generally carried out by using pressure or temperature. In a preferred embodiment the invention, optionally granulating the mixture from step (al) can be performed, for example, by "slugging", using a large heavy-duty rotary press and breaking up the slugs to granulates with a hammer mill or by roller compaction, using for example roller compactors by Powtec or Alexanderwerk. The granulates are then optionally screened.
In step (a3) the mixture resulting from step (al) or optionally the granulates from step (a2) can be further processed into a dosage form. For this purpose, said mixture or said granulates can, for example, be filled into sachets or capsules.
In a preferred embodiment, step (a3) can include compressing the mixture resulting from step (al) or optionally the granulates from step (a2) and optionally further excipient(s), such as lubricant, into tablets. The compression of the mixture of step (al) can preferably be a direct compression. This direct compression step can preferably be carried out on a rotary press, for example on a Fette® 102i (Fette GmbH, Germany) or a Riva® piccola (Riva, Argentina). If a rotary press is applied, the main compaction force can range from 1 to 50 kN, preferably from 2 to 40 kN, more preferably form 3 to 30 kN.
In an alternative embodiment the granulates from step (a2) can be compressed into tablets. Further, the granulates could be filled into capsules or other dosage forms like stick-packs or sachets.
In step (a4) the tablet can optionally be film-coated. Film-coating is preferred for tablets for peroral use. Hence, in a preferred embodiment the composition of the present invention is in form of a peroral tablet or filled into a capsule. In another preferred embodiment, the composition of the present invention is in form of an effervescent tablet to be dissolved in a liquid. Alternatively, the composition of the present invention can be an oral dosage form, wherein the composition is filled into suitable devices like sachets or stick-packs.
In a preferred embodiment the dosage form may be administered in a single daily dose or in divided doses of two to six times a day. In certain embodiments of the invention the dosage form of edoxaban may be administered less frequently then once daily, e.g. every second, third, or fourth day. In particular, the dosage form of the present invention is administered once or twice daily. It has been unexpectedly found that the dosage form of the present invention can be administered independently from the meals of the patient, i.e. the dosage forms of the present invention are suitable to be administered before, during or after the meals.
In a preferred embodiment, the dosage forms of the invention are administered daily at a dose of from about 5 to about 120 mg/d, preferably 10 to 90 mg/d, more preferably 15 to 60 mg/d.
The dosage form of the present invention preferably shows superior dissolution and absorption characteristics upon administration, leading to desirable plasma values like desirable AUC (area under the curve from 0 to 48 hours after oral administration), Cmax and Tmax values. Preferably, administration of the dosage form of the present invention results in a Tmax value of 0.5 to 3 hours, more preferably of 0.75 to 1.5 hours. Preferably, administration of the dosage form of the present invention (in a strength of 30 mg calculated for the free base of Edoxaban) results in a Cmax value of 100 to 300 ng/ l, more preferably 150 to 250 ng/ml. Preferably, administration of the dosage form of the present invention (in a strength of 60 mg calculated for the free base of Edoxaban) results in a Cma value of 150 to 500 ng/ml, more preferably 200 to 350 ng/ml. Preferably, administration of the dosage form of the present invention (in a strength of 30 mg calculated for the free base of Edoxaban) results in a AUC value of 500 to 3000 ng h/ml, more preferably 750 to 1500 ng h/ml. The plasma values are an average of ten single measurement values, determined upon administration to 10 male humans having a body weight of about 75 kg.
The dosage forms of the present invention are used in the management (e.g. in the prevention or treatment) of thrombotic disorders. Hence, a further subject of the invention is a dosage form according to the invention for managing thrombotic disorders. It has been found, that patients, having at least one of the following risks, can be advantageously treated: age 66 years or older, elevated cardiac biomarkers, cerebrovascular diseases, peripheral vascular disease, non- revascularizable multivessel coronary artery disease, renal insufficiency and diabetes mellitus. Preferably, the dosage form according to the invention can be used for preventing or treating thrombotic disorders, wherein the dosage form is administered in a patient suffering from diabetes mellitus.
A further subject of the invention is the use of a C02-forming agent and/or an inorganic filler for producing an antithrombotic-drug-containing dosage form, preferably edoxaban-containing dosage form which is free of sugar alcohol.
All explanations given above for preferred embodiments (preferred excipients, etc.) also apply to said use.
EXAMPLES
Example 1: Dosage form by direct compression
4.05 g edoxaban tosylate monohydrate, 3.00 g cornstarch (Amidon DE Mais B) and 0.50 g sodium lauryl sulfate were sieved (mesh size # 800 μιη) and blended in a Turbula® mixer for 15 minutes. 5.00 g saccharose, 7.50 g tartaric acid, 5.00 g sodium bicarbonate and 0.10 g silica (Aerosil®200) were added through a sieve (mesh size # 800 μιη) and blended with the premix for further 15 minutes. 0.70 g sodium stearyl fumarate (PRUV ) were added through a sieve (mesh size # 500 μπι) and blended for 3 minutes to obtain the final blend for compression. The final blend is compressed on an excenter press (Korsch EKO) to tablets, each containing
Edoxaban tosylate monohydrate 40.46 mg Cornstarch 30.00 mg Saccharose 50.00 mg Tartaric acid 75.00 mg Sodium bicarbonate 50.00 mg Sodium lauryl sulfate 5.00 mg Silica 1.00 mg
Sodium stearyl fumarate 7.00 mg Example 2: Dosage form by direct compression
4.05 g edoxaban tosylate monhydrate and 5.00 g sodium bicarbonate were sieved (mesh size # 800 μηι) and milled in a ball mill. After sieving the milled premix (mesh size # 800 μπι) into a Turbula® mixer, 3.00 g cornstarch (Amidon DE Mais B), 5.00 g saccharose, 7.50 g tartaric acid and 0.10 g silica (Aerosil®200) were added through a sieve (mesh size # 800 μηι) and the mixture was blended for 15 minutes. 0.70 g sodium stearyl fumarate (PRUV®) were further added through a sieve (mesh size # 500 μηι) and blended for further 3 minutes to obtain the final blend for compression. The final blend is compressed on an excenter press (Korsch EKO) to tablets, each containing
Edoxaban tosylate monohydrate 40.46 mg
Cornstarch 30.00 mg
Saccharose 50.00 mg
Tartaric acid 75.00 mg Sodium bicarbonate 50.00 mg
Silica 1.00 mg
Sodium stearyl fumarate 7.00 mg
Example 3: Dosage form by direct compression
4.05 g edoxaban tosylate monohydrate and 5.00 g sodium bicarbonate were sieved (mesh size # 800 μηι) and milled in a ball mill. After sieving the milled premix (mesh size # 800 μπι) into a Turbula® mixer 3.00 g corn starch (Amidon DE Mais B), 5.00 g saccharose, 7.50 g tartaric acid, 0.50 g sodium lauryl sulfate and 0.10 g silica (Aerosil®200) were added through a sieve (mesh size # 800 μηι) and the mixture was blended for 15 minutes. 0.70 g sodium stearyl fumarate (PRUV ) were further added through a sieve (mesh size # 500 μπι) and blended for further 3 minutes to obtain the final blend for compression. The final blend is compressed on an excenter press (Korsch EK0) to tablets, each containing
Edoxaban tosylate monohydrate 40.46 mg
Cornstarch 30.00 mg
Saccharose 50.00 mg
Tartaric acid 75.00 mg
Sodium bicarbonate 50.00 mg
Sodium lauryl sulfate 5.00 mg
Silica 1.00 mg
Sodium stearyl fumarate 7.00 mg

Claims

Claims
1. Composition comprising edoxaban and a C02-forming agent.
2. Composition according to claim 1 , wherein the average particle size (D50) of edoxaban is from 0.1 to 150 μπι.
3. Composition according to claim 1 or 2, containing edoxaban in an amount of from 10 to 100 mg.
4. Composition according to any one of claims 1 to 3, wherein the ratio of edoxaban to C02-forming agent is from 5 : 1 to 1 : 2.
5. Composition according to any one of claims 1 to 4, further comprising an organic acid.
6. Composition according to any one of claims 1 to 5 comprising one or more further pharmaceutical excipient(s).
7. Composition according to claim 6, wherein one pharmaceutical excipient is a binder.
8. Composition according to claim 7, wherein the binder has a water-solubility of 5 to 1000 mg/ml.
9. Composition according to any one of claims 1 to 7 comprising edoxaban, C02-forming agent, binder, filler, glidant, surfactant and/or lubricant.
10. Composition according to any one of claims 1 to 8 comprising
1.5 to 60 wt.% edoxaban;
1.0 to 35 wt.% C02-forming agent; 0 to 30 wt.% binder;
0 to 50 wt.% filler;
2 to 35 wt.% organic acid;
0.05 to 5.0% by weight surfactant;
0 to 3 wt.%, glidant;
0 to 4% by weight lubricant,
based on the total weight of the composition.
Dosage form comprising a composition according to any one of claims 1 to
12. Dosage form according to claim 1 1 , wherein the dosage form is a tablet, having a hardness of 50 to 250 N, a friability of less then 5 % and a content uniformity of 95 to 105 %.
13. Dosage form according to claim 1 1 or 12, wherein the dosage form provides immediate release of edoxaban.
14. A method of preparing a dosage form according to any one of the claims 1 1 to 13 comprising the steps of
(al) mixing edoxaban, C02-forming agent and optionally one ore more pharmaceutical excipient(s),
(a2) optionally granulating the mixture from (al),
(a3) processing the mixture resulting from step (al) or the granulates from (a2) into a dosage form, and
(a4) optionally film-coating the dosage form.
15. Use of a C02-forming agent and/or inorganic filler for producing antithrombotic-drug-containing dosage form which is free of sugar alcohol.
PCT/EP2012/003512 2011-08-22 2012-08-17 Composition comprising edoxaban WO2013026553A1 (en)

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US61/526,065 2011-08-22
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EP11006839.2 2011-08-22

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CN105434340A (en) * 2015-12-18 2016-03-30 北京万全德众医药生物技术有限公司 P-toluene sulfonic acid edoxaban oral solution and preparing method thereof
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WO2020022824A1 (en) * 2018-07-27 2020-01-30 보령제약 주식회사 Pharmaceutical formulation comprising edoxaban and preparation method therefor
CN112791057A (en) * 2021-02-07 2021-05-14 齐飞 Slow release preparation containing edoxaban and preparation method thereof
WO2022129535A1 (en) 2020-12-18 2022-06-23 Krka, D.D., Novo Mesto Edoxaban formulation containing no sugar alcohols
EP4183390A1 (en) * 2021-11-22 2023-05-24 Intas Pharmaceuticals Limited An orodispersible pharmaceutical dosage form of edoxaban
WO2023089575A1 (en) * 2021-11-22 2023-05-25 Intas Pharmaceuticals Ltd. An orodispersible pharmaceutical dosage form of edoxaban

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Publication number Priority date Publication date Assignee Title
CN103919746A (en) * 2014-04-17 2014-07-16 山东省医药工业研究所 Edoxaban sustained release tablet and preparation method thereof
JP2017523149A (en) * 2014-08-06 2017-08-17 サンド・アクチエンゲゼルシヤフト Edoxaban pharmaceutical composition
CN105434340A (en) * 2015-12-18 2016-03-30 北京万全德众医药生物技术有限公司 P-toluene sulfonic acid edoxaban oral solution and preparing method thereof
WO2020022824A1 (en) * 2018-07-27 2020-01-30 보령제약 주식회사 Pharmaceutical formulation comprising edoxaban and preparation method therefor
WO2022129535A1 (en) 2020-12-18 2022-06-23 Krka, D.D., Novo Mesto Edoxaban formulation containing no sugar alcohols
CN112791057A (en) * 2021-02-07 2021-05-14 齐飞 Slow release preparation containing edoxaban and preparation method thereof
CN112791057B (en) * 2021-02-07 2022-03-18 齐飞 Slow release preparation containing edoxaban and preparation method thereof
EP4183390A1 (en) * 2021-11-22 2023-05-24 Intas Pharmaceuticals Limited An orodispersible pharmaceutical dosage form of edoxaban
WO2023089575A1 (en) * 2021-11-22 2023-05-25 Intas Pharmaceuticals Ltd. An orodispersible pharmaceutical dosage form of edoxaban

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