METHOD FOR PRODUCING APIXABAN GRANULES

Description

[0001] The present invention relates to a process for the preparation of a pharmaceutical granulate containing apixaban or a salt thereof as active ingredient.

[0002] Apixaban is the international nonproprietary name (INN ( i nternational n onproprietary n ame)) for 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbamide, which has the following structural formula: Apixaban is a drug from the group of anticoagulants, which is used for Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation and one or more risk factors, such as a history of stroke or TIA (transient ischemic attack), age ≥ 75 years, hypertension, diabetes mellitus, symptomatic heart failure (NYHA class ≥ II); treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) as well as prevention of recurrent DVT and PE in adults; thromboembolism prophylaxis after knee and hip replacement. The effect of apixaban is based on the selective inhibition of the enzyme Factor Xa, which is involved in blood clotting.

[0003] Apixaban is marketed under the brand name Eliquis®< in the form of oral film-coated tablets in strengths of 2.5 mg and 5 mg. Apixaban is contained in Eliquis®< in the free base form. According to the European Medicines Agency (EMA) assessment report on Eliquis®< dated June 20, 2011 (see section 2, "Scientific Discussion"), these oral film-coated tablets are manufactured via an intermediate step of a dry granulation process. It is stated that using apixaban dry granules, tablets can be produced that exhibit sufficiently consistent dissolution rates for immediate drug release. However, this requires the active ingredient to be used in a specific particle size distribution.

[0004] EP 2 907 507 A1 discloses apixaban tablets containing a surfactant in addition to a low-viscosity polymer. Sodium lauryl sulfate is used as the surfactant and povidone (polyvinylpyrrolidone) as the low-viscosity polymer.

[0005] The object of the present invention is therefore to provide a process for producing a pharmaceutical granulate containing apixaban or a salt thereof as the active ingredient, in which the active ingredient can be used largely independently of its particle size distribution, but the resulting granulate can nevertheless be used to produce dosage forms which show sufficiently consistent active ingredient dissolution rates for an immediate release of the active ingredient.

[0006] The problem is solved by a method of the type mentioned above, comprising the steps of a) providing a solvent; b) combining the solvent with the active ingredient to obtain a granulating liquid; c) wet granulating a powdered material using the granulating liquid, wherein an amphiphilic substance is contained in the solvent and the amphiphilic substance is a polyvinylcaprolactam polyvinyl acetate-polyethylene glycol graft copolymer or is selected from the group consisting of caprylocaproyl macrogol-8-glyceride, lauroyl macrogol-32-glyceride, stearoyl macrogol-32-glyceride, oleoyl macrogol-6-glyceride, linoleoyl macrogol-6-glyceride and lauroyl macrogol-6-glyceride, and the active ingredient is contained in the solvent dissolved, dissolved and dispersed, dissolved and suspended or dissolved, dispersed and suspended.

[0007] Surprisingly, it was found that in the process according to the invention, the active ingredient can be used largely independently of its particle size distribution, but nevertheless granules result by means of which dosage forms can be produced that show sufficiently consistent active ingredient dissolution rates for an immediate release of the active ingredient.

[0008] Since the active ingredient can be used in the process according to the invention largely independently of its particle size distribution, the process according to the invention is relatively cost-effective. Furthermore, any subsequent grinding of agglomerated active ingredient particles with a previously defined particle size distribution is no longer necessary with regard to the process according to the invention.

[0009] Furthermore, it has been advantageously found that the granules obtainable by the process according to the invention and dosage forms produced therefrom are characterized by a relatively high uniformity of the active ingredient content according to the European Pharmacopoeia, 8th edition, 4th supplement, chapters 2.9.6 and 2.9.40.

[0010] A solvent is used in the process according to the invention. According to the invention, the solvent used can in principle be any solvent in which apixaban or the pharmaceutically acceptable salt thereof is soluble and by means of which wet granulation of the powdered material, which is generally formed from one or more pharmaceutically acceptable excipients such as microcrystalline cellulose and / or lactose, can be carried out. Preferred solvents according to the invention include dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethanol, isopropanol, or water, or mixtures of two or more of the aforementioned. To improve the solubility of the apixaban or the pharmaceutically acceptable salt thereof, the solvent can additionally comprise one or more solubilizing agents.

[0011] In the process according to the invention, the solvent is combined with the active ingredient, wherein at least part of the active ingredient is dissolved in the solvent to obtain a granulation liquid. This means that the active ingredient is soluble in the solvent and that, under given conditions, it is preferably also dissolved as completely as possible. In view of the above-mentioned technical advantages of the present invention, it is generally preferred if the solubility of the active ingredient in the solvent is as high as possible. However, it is sufficient and preferred according to the invention if the solubility of the active ingredient in the solvent at a temperature of 50 °C is greater than 0.01 mg / ml, further preferably greater than 0.1 mg / ml, more preferably greater than 0.2 mg / ml and even more preferably greater than 0.5 mg / ml.

[0012] The powdered material to be used in the process according to the invention can, in principle, be of any nature, but it must be capable of being processed into moist granules. Examples of powdered materials include conventional pharmaceutical excipients such as microcrystalline cellulose, lactose, Cellactose®, crosscarmellose sodium, sodium carboxymethyl starch, polyvinylpyrrolidone, silicon dioxide, methylcellulose, and ethylcellulose, as well as mixtures of two or more of the aforementioned excipients.

[0013] According to the method according to the invention, an amphiphilic substance is preferably contained in dissolved form in the solvent. Amphiphilic substances can improve the solubility of the active ingredient in the solvent. Amphiphilic substances are known in the art. These are molecules that have both hydrophilic and hydrophobic regions and are therefore relatively soluble in both polar and nonpolar solvents.

[0014] According to a preferred embodiment of the process according to the invention, the solvent is or comprises water. Compared to other solvents, water is physiologically acceptable. Since the solvent cannot be completely removed from the granules resulting from the process according to the invention, the use of water results in the resulting granules being characterized by increased physiological tolerance, which generally increases the larger the proportion of the solvent formed by water.

[0015] In the process according to the invention, it is provided that the active ingredient is contained in the solvent in dissolved, dissolved and dispersed, dissolved and suspended, or dissolved, dispersed and suspended form. As already explained above, in the process according to the invention the solvent is combined with the active ingredient, at least part of the active ingredient being dissolved in the solvent. The active ingredient is preferably dissolved as completely as possible in the solvent, i.e., if appropriate, up to the solubility limit. If, for example, with regard to process engineering aspects of wet granulation, the amount of active ingredient per unit volume of solvent is desired to be higher than the maximum solubility, the active ingredient can be present in the solvent not only in solution but also in dispersed and / or suspended form.

[0016] According to the method according to the invention, the active ingredient is apixaban. In principle, the active ingredient can be used in the method according to the invention in the form of the free apixaban base or in the form of a pharmaceutically acceptable salt thereof. However, with regard to the stability of the active ingredient in the resulting granules, it is preferred if the active ingredient is used in the form of the free apixaban base in the method according to the invention.

[0017] According to a further preferred embodiment of the process according to the invention, the amphiphilic substance is a non-ionic substance. It has been found that non-ionic amphiphilic substances, in particular, can facilitate relatively easy process control in the wet granulation process step.

[0018] An amphiphilic substance can be selected from the group consisting of polymers, surfactants, monoglycerides, diglycerides, triglycerides, and phospholipids. Amphiphilic polymers, surfactants, monoglycerides, diglycerides, triglycerides, and phospholipids can ensure sufficient solubilization of the active ingredient in the solvent, especially in water.

[0019] An amphiphilic substance can be a graft copolymer, a block copolymer, or a graft and block copolymer. These polymers can ensure sufficient solubilization of the active ingredient in the solvent and also ensure good processability of the granulation liquid during wet granulation.

[0020] According to the process according to the invention, the amphiphilic substance is, for example, a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. Said polymer can achieve sufficient solubilization of the active ingredient in the solvent and exhibits sufficiently consistent dissolution rates of the active ingredient with regard to immediate drug release. In this context, the polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer Soluplus® from BASF AG, with an average molecular weight of 90,000 to 140,000 g / mol, is particularly preferred according to the invention.

[0021] An amphiphilic substance can be selected from the group consisting of polyoxyethylene fatty acid esters, polyoxyethylene fatty acid ethers, and polyethylene glycol fatty acid esters. These amphiphilic substances can ensure sufficient solubilization of the active ingredient in the solvent and also ensure good processability of the granulation liquid during wet granulation.

[0022] According to the method according to the invention, the amphiphilic substance is further selected from the group consisting of caprylocaproyl macrogol-8-glyceride, lauroyl macrogol-32-glyceride, stearoyl macrogol-32-glyceride, oleoyl macrogol-6-glyceride, linoleoyl macrogol-6-glyceride, and lauroyl macrogol-6-glyceride, preferably consisting of lauroyl macrogol-32-glyceride. The amphiphilic substances mentioned can bring about sufficient solubilization of the active ingredient in the solvent and exhibit very consistent dissolution rates of the active ingredient with regard to immediate drug release. In this context, it is particularly preferred according to the invention if the lauroyl macrogol-32-glyceride is used in the form of the product Gelucire®< 44 / 14 from Gattefossé. Gelucire ®< 44 / 14 is a mixture of PEG esters, i.e. lauroyl macrogol 32-glyceride, a small glyceride fraction and free PEG.

[0023] According to a further preferred embodiment of the method according to the invention, the amphiphilic substance has an HLB value of 9 to 18, preferably an HLB value of 9 to 12. Amphiphilic substances with HLB (hydrophilic-lipophilic balance) values ​​in the stated ranges can achieve sufficient solubilization of the active ingredient in the solvent. HLB values ​​for amphiphilic substances are calculated using recognized methods and are known in the art.

[0024] According to a further preferred embodiment of the method according to the invention, the active ingredient and solvent are present in the granulation liquid in a weight ratio of 1:100 to 1:2500, more preferably in a weight ratio of 1:200 to 1:1000, and more preferably in a weight ratio of 1:200 to 1:600. This ensures good processability of the granulation liquid in the wet granulation step.

[0025] According to a further preferred embodiment of the method according to the invention, it is provided that the active ingredient and solvent are present in the granulation liquid in a weight ratio of 1:10 to 1:200, more preferably in a weight ratio of 1:10 to 1:100, and more preferably in a weight ratio of 1:15 to 1:50. This also ensures good processability of the granulation liquid in the wet granulation step.

[0026] According to a further preferred embodiment of the method according to the invention, it is provided that the active ingredient and amphiphilic substance are present in the granulation liquid in a weight ratio of 1:2 to 1:200, more preferably in a weight ratio of 1:4 to 1:120, and more preferably in a weight ratio of 1:4 to 1:80. This largely ensures sufficient solubility of the active ingredient in the solvent.

[0027] According to a further preferred embodiment of the method according to the invention, the active ingredient and amphiphilic substance are present in the granulation liquid in a weight ratio of 40:1 to 1:200, more preferably in a weight ratio of 30:1 to 1:120, and more preferably in a weight ratio of 20:1 to 1:80. This also largely ensures sufficient solubility of the active ingredient in the solvent. In this context, it is further preferred according to the invention if the powdered material also comprises the amphiphilic substance, specifically from 0.5 wt.% to 20 wt.%, and preferably from 1.0 wt.% to 10 wt.%.

[0028] According to a further preferred embodiment of the method according to the invention, it is provided that the combination of the solvent with the active ingredient takes place at a temperature above 30 °C, more preferably at a temperature of 40 °C to 80 °C, and more preferably at a temperature of 45 °C to 60 °C. This further improves the solubility of the active ingredient in the solvent without having to accept disadvantages with regard to the stability of the active ingredient.

[0029] According to a further preferred embodiment of the method according to the invention, it is provided that the method further comprises the step of d) drying the granules.

[0030] According to a further preferred embodiment of the method according to the invention, it is provided that the method further comprises the step of e) processing the granules into a dosage form.

[0031] According to the invention, the step of processing the granules into a dosage form can preferably be carried out by filling the granules into a capsule, with or without additional pharmaceutical excipients, or by compressing the granules into a tablet, with or without additional pharmaceutical excipients. The granules can also be filled into sachets, with or without additional excipients.

[0032] According to a further preferred embodiment of the method according to the invention, it is provided that the dosage form is free of sodium dodecyl sulfate.

[0033] According to a further preferred embodiment of the method according to the invention, it is provided that the dosage form is an immediate release dosage form.

[0034] A typical method according to the invention comprises the steps of a) providing an aqueous solvent comprising an amphiphilic substance selected from the group consisting of a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or a lauroyl macrogol-32 glyceride; b) combining the solvent with the active ingredient apixaban to obtain a granulating liquid; c) wet granulating a powdered material using the granulating liquid; and optionally d) drying the granules; and optionally e) processing the granules into a dosage form.

[0035] In the context of the aforementioned typical process according to the invention, an aqueous solvent is understood to mean a solvent whose liquid component (without amphiphilic substance) consists of at least 50 wt.% water, preferably at least 70 wt.% water, more preferably at least 90 wt.% water, and even more preferably at least 95 wt.% water. In this context, it is particularly preferred according to the invention if the liquid component consists of at least 99 wt.% water and even more preferably 100 wt.% water.

[0036] In addition to water, the liquid component may also contain a certain proportion of one or more water-miscible liquid organic components. Examples of such organic components include DMSO, DMF, ethanol, and isopropanol.

[0037] The present invention further relates to a granulate obtainable by the process according to the invention.

[0038] The present invention further relates to a dosage form obtainable by the process according to the invention or containing a granulate according to the invention.

[0039] The following embodiments serve to explain the invention. Example 1 (not according to the invention):

[0040] Film-coated tablets in the dosage form with the formulation given in Table 1 were manufactured using the granules (Phase I) manufactured using the process below. Table 1: ingredient Phase I Cellactose (composed of 25% by weight powdered cellulose and 75% by weight lactose monohydrate) 63.90 mg Crosscarmellose sodium 4.00 mg Apixaban (free base) 2.50 mg Dimethyl sulfoxide (DMSO, no longer contained in the final product) qs Phase II Crosscarmellose sodium 4.00 mg Silicon dioxide 4.80 mg Magnesium stearate 0.80 mg Final tablet weight 80.00 mg Film coating Opadry ®< (colored; composed of hypromellose, macrogol, titanium dioxide, iron oxide, demineralized water (not contained in the final product)) 2.50 mg Final weight of film-coated tablet 82.50 mg

[0041] The film-coated tablets were produced by first thoroughly mixing the filler cellactose and the disintegrant crosscarmellose sodium (both substances form the powdered material). The resulting mixture was wet-granulated using a solution of apixaban in DMSO (5 mg / ml) as the granulating liquid to obtain the granules according to the invention (Phase I). The resulting granules were dried, sieved, thoroughly mixed with the disintegrant crosscarmellose sodium, the flow agent silicon dioxide, and the lubricant magnesium stearate, and the resulting mixture was compressed into round, flat, biplane tablet cores using a conventional tablet press. The tablet cores thus produced were film-coated. Example 2 (not according to the invention):

[0042] Film-coated tablets in the dosage form with the formulation given in Table 2 were manufactured using the granules (Phase I) produced using the process. Table 2: ingredient Phase I Cellactose (composed of 25% by weight powdered cellulose and 75% by weight lactose monohydrate) 63.90 mg Crosscarmellose sodium 4.00 mg Apixaban (free base) 2.50 mg Mixture of DMSO and water in a weight ratio of 1:1 (DMSO and water are no longer contained in the final product) qs Phase II Crosscarmellose sodium 4.00 mg Silicon dioxide 4.80 mg Magnesium stearate 0.80 mg Final tablet weight 80.00 mg Film coating Opadry ®< (colored; composed of hypromellose, macrogol, titanium dioxide, iron oxide, demineralized water (not contained in the final product)) 2.50 mg Final weight of film-coated tablet 82.50 mg

[0043] The film-coated tablets were produced analogously to Example 1, whereby the powdered mixture was wet granulated using a solution of apixaban in DMSO / water (0.5 mg / ml) as the granulating liquid. Example 3 (not according to the invention):

[0044] Film-coated tablets in the dosage form with the formulation given in Table 3 were manufactured using the granules (Phase I) produced using the process. Table 3: ingredient Phase I Cellactose (composed of 25% by weight powdered cellulose and 75% by weight lactose monohydrate) 63.90 mg Crosscarmellose sodium 4.00 mg Apixaban (free base) 2.50 mg Dimethylformamide (DMF, in the final product no longer qs contain) Phase II Crosscarmellose sodium 4.00 mg Silicon dioxide 4.80 mg Magnesium stearate 0.80 mg Final tablet weight 80.00 mg Film coating Opadry ®< (colored; composed of hypromellose, macrogol, titanium dioxide, iron oxide, demineralized water (not contained in the final product)) 2.50 mg Final weight of film-coated tablet 82.50 mg

[0045] The film-coated tablets were produced analogously to Example 1, whereby the powdered mixture was wet granulated using a solution of apixaban in DMF (3.0 mg / ml) as the granulating liquid. Example 4 (not according to the invention):

[0046] Film-coated tablets in the dosage form with the formulation given in Table 4 were manufactured using the granules (Phase I) produced using the process. Table 4: ingredient Phase I Cellactose (composed of 25% by weight powdered cellulose and 75% by weight lactose monohydrate) 63.90 mg Crosscarmellose sodium 4.00 mg Apixaban (free base) 2.50 mg Mixture of DMF and water in a weight ratio of 1:1 (DMF and water are no longer contained in the final product) qs Phase II Crosscarmellose sodium 4.00 mg Silicon dioxide 4.80 mg Magnesium stearate 0.80 mg Final tablet weight 80.00 mg Film coating Opadry ®< (colored; composed of hypromellose, macrogol, titanium dioxide, iron oxide, demineralized water (not contained in the final product)) 2.50 mg Final weight of film-coated tablet 82.50 mg

[0047] The film-coated tablets were produced analogously to Example 1, whereby the powdered mixture was wet granulated using a solution of apixaban in DMF / water (0.5 mg / ml) as the granulating liquid. Embodiment 5 (according to the invention):

[0048] Film-coated tablets were produced as a dosage form according to the invention with the formulation given in Table 5 using the granules according to the invention (Phase I) which were manufactured using the process according to the invention. Table 5: ingredient Phase I Cellactose (composed of 25% by weight powdered cellulose and 75% by weight lactose monohydrate) 33.90 mg Crosscarmellose sodium 4.00 mg Apixaban (free base) 2.50 mg Soluplus ®< (BASF, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer with a medium 200.00 mg Molecular weight from 90000 to 140000 g / mol) Water (no longer contained in the final product) qs Phase II Crosscarmellose sodium 4.00 mg Silicon dioxide 4.80 mg Magnesium stearate 0.80 mg Final tablet weight 250.00 mg Film coating Opadry ®< (colored; composed of hypromellose, macrogol, titanium dioxide, iron oxide, demineralized water (not contained in the final product)) 5.00 mg Final weight of film-coated tablet 255.00 mg

[0049] The film-coated tablets were produced analogously to Example 1, whereby the powdered mixture was wet granulated using a solution / dispersion of apixaban in water / Soluplus ®< (2.5 mg / ml) as the granulating liquid.

[0050] The granulation liquid was prepared by heating the solvent, i.e., a 20 wt.% solution of Soluplus ®< as an amphiphilic substance in water, to a temperature of 50 °C and adding 2.5 mg of apixaban per ml of solvent. After exposure of the granulation liquid to an Ultra-Turrax ®< for a period of 4 hours, approximately 54% of the apixaban used was dissolved in the solvent, and the remainder was dispersed in the solvent. Embodiment 6 (according to the invention):

[0051] Film-coated tablets were produced as a dosage form according to the invention with the formulation given in Table 6 using the granules according to the invention (Phase I) which were manufactured using the process according to the invention. Table 6: ingredient Phase I Cellactose (composed of 25% by weight powdered cellulose and 75% by weight lactose monohydrate) 33.90 mg Crosscarmellose sodium 4.00 mg Apixaban (free base) 2.50 mg Gelucire ®< 44 / 14 (Gattefossé, Gelucire ®< 44 / 14 is a mixture of PEG esters (ie lauroyl-macrogol-32-glyceride), a small glyceride fraction and free PEG 100.00 mg Water (no longer contained in the final product) qs Phase II Crosscarmellose sodium 4.00 mg Silicon dioxide 4.80 mg Magnesium stearate 0.80 mg Final tablet weight 150.00 mg Film coating Opadry ®< (colored; composed of hypromellose, macrogol, titanium dioxide, iron oxide, demineralized water (not contained in the final product)) 3.00 mg Final weight of film-coated tablet 153.00 mg

[0052] The film-coated tablets were produced analogously to Example 1, whereby the powdered mixture was wet granulated using a solution / dispersion of apixaban in water / Gelucire ®< (2.5 mg / ml) as the granulating liquid.

[0053] Said granulation liquid was prepared by heating the solvent, ie a 10 wt% solution of Gelucire ®< as amphiphilic substance in water, to a temperature of 50 °C and adding 2.5 mg apixaban per ml of solvent. Embodiment 7 (according to the invention):

[0054] Film-coated tablets were produced as a dosage form according to the invention with the formulation given in Table 7 using the granules according to the invention (Phase I) which were manufactured using the process according to the invention. Table 7: ingredient Phase I microcrystalline cellulose 49.00 mg Na-carboxymethyl starch 3.00 mg Apixaban (free base) 2.50 mg Soluplus ®< (BASF, polyvinylcaprolactam polyvinyl acetate-polyethylene glycol graft copolymer with an average molecular weight of 90,000 to 140,000 g / mol) 20.00 mg Water (no longer contained in the final product) qs Phase II microcrystalline cellulose 22.50 mg Silicon dioxide 2.00 mg Magnesium stearate 1.00 mg Final tablet weight 100.00 mg Film coating Opadry ®< (colored; composed of hypromellose, macrogol, titanium dioxide, iron oxide, demineralized water (not contained in the final product)) 5.00 mg Final weight of film-coated tablet 105.00 mg

[0055] The film-coated tablets were produced analogously to Example 1, whereby the powdered mixture was wet granulated using a solution / dispersion of apixaban in water / Soluplus ®< (2.5 mg / ml) as the granulating liquid.

[0056] The granulation liquid was prepared by heating the solvent, i.e., a 2 wt.% solution of Soluplus ®< as an amphiphilic substance in water, to a temperature of 50 °C and adding 2.5 mg of apixaban per ml of solvent. After exposure of the granulation liquid to an Ultra-Turrax ®< for a period of 4 hours, a portion of the apixaban used was dissolved in the solvent, and the remainder was dispersed in the solvent. Embodiment 8 (according to the invention):

[0057] Film-coated tablets were produced as a dosage form according to the invention with the formulation given in Table 8 using the granules according to the invention (Phase I) which were manufactured using the process according to the invention. Table 8: ingredient Phase I microcrystalline cellulose 59.00 mg Na-carboxymethyl starch 3.00 mg Apixaban (free base) 2.50 mg Gelucire ®< 44 / 14 (Gattefossé, Gelucire ®< 44 / 14 is a mixture of PEG esters (ie lauroyl-macrogol-32-glyceride), a small glyceride fraction and free PEG 10.00 mg Water (no longer contained in the final product) qs Phase II microcrystalline cellulose 22.50 mg Silicon dioxide 2.00 mg Magnesium stearate 1.00 mg Final tablet weight 100.00 mg Film coating Opadry ®< (colored; composed of hypromellose, macrogol, titanium dioxide, iron oxide, demineralized water (not contained in the final product)) 5.00 mg Final weight of film-coated tablet 105.00 mg

[0058] The film-coated tablets were produced analogously to Example 1, whereby the powdered mixture was wet granulated using a solution / dispersion of apixaban in water / Gelucire ®< (2.5 mg / ml) as the granulating liquid.

[0059] Said granulation liquid was prepared by heating the solvent, ie a 1 wt% solution of Gelucire ®< as amphiphilic substance in water, to a temperature of 50 °C and adding 2.5 mg apixaban per ml of solvent. Embodiment 9 (according to the invention):

[0060] Tablets were produced as a dosage form according to the invention with the formulation given in Table 9 using the granules according to the invention (Phase I) which were manufactured using the process according to the invention. Table 9: ingredient Phase I Microcrystalline cellulose (Avicel PH 101) 64.00 mg Na-carboxymethyl starch (Primojel) 3.00 mg Apixaban (free base) 2.50 mg Povidone 30 (Kollidon K-30) 1,50 Soluplus ®< (BASF, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer with a medium 5.00 mg Molecular weight from 90000 to 140000 g / mol) Water (no longer contained in the final product) 45,00 Phase II Microcrystalline cellulose (Avicel PH 102) 21.00 mg Silicon dioxide, highly disperse (Aerosil 200) 2.00 mg Magnesium stearate 1.00 mg Final tablet weight (without film) 100.00 mg

[0061] The tablets were manufactured analogously to Example 1, whereby the powdered mixture was wet granulated using a solution / dispersion of apixaban in water / Soluplus ®< as granulating liquid.

[0062] The granulation liquid was prepared by first dissolving the amphiphilic Soluplus® in water using an Ultra-Turrax®. Apixaban was then finely dispersed in the resulting solution using an Ultra-Turrax®. The resulting suspension was stirred overnight at 50 °C using a magnetic stirrer. Embodiment 10 (according to the invention):

[0063] Tablets were produced as a dosage form according to the invention with the formulation given in Table 10 using the granules according to the invention (Phase I) which were manufactured using the process according to the invention. Table 10: ingredient Phase I Microcrystalline cellulose (Avicel PH 101) 128.00 mg Na-carboxymethyl starch (Primojel) 6.00 mg Apixaban (free base) 5.00 mg Povidone 30 (Kollidon K-30) 3,00 Soluplus ®< (BASF, polyvinylcaprolactam- 10.00 mg polyvinyl acetate-polyethylene glycol graft copolymer with an average molecular weight of 90,000 to 140,000 g / mol) Water (no longer contained in the final product) 90,00 Phase II Microcrystalline cellulose (Avicel PH 102) 42.00 mg Silicon dioxide, highly disperse (Aerosil 200) 4.00 mg Magnesium stearate 2.00 mg Final tablet weight (without film) 200.00 mg

[0064] The tablets were manufactured analogously to Example 1, whereby the powdered mixture was wet granulated using a solution / dispersion of apixaban in water / Soluplus ®< as granulating liquid.

[0065] The granulation liquid was prepared by first dissolving the amphiphilic Soluplus® in water using an Ultra-Turrax®. Apixaban was then finely dispersed in the resulting solution using an Ultra-Turrax®. The resulting suspension was stirred overnight at 50 °C using a magnetic stirrer. Embodiment 11 (according to the invention):

[0066] Tablets were produced as a dosage form according to the invention with the formulation given in Table 11 using the granules according to the invention (Phase I) which were manufactured using the process according to the invention. Table 11: ingredient Phase I Microcrystalline cellulose (Avicel PH 101) 87.87 mg Croscarmellose 4.00 mg Apixaban (free base) 2.50 mg Soluplus ®< (BASF, polyvinylcaprolactam polyvinyl acetate-polyethylene glycol graft copolymer with an average molecular weight of 90,000 to 140,000 g / mol) 0.13 mg Soluplus ®< (BASF, polyvinylcaprolactam polyvinyl acetate-polyethylene glycol graft copolymer with an average molecular weight of 90,000 to 140,000 g / mol) 5.00 mg Water (no longer contained in the final product) 45,00 Phase II Magnesium stearate 0.50 mg Final tablet weight (without film) 100.00 mg

[0067] The tablets were manufactured analogously to Example 1, whereby the powdered mixture was wet granulated using a solution / dispersion of apixaban in water / 0.13 mg Soluplus ®< as granulating liquid.

[0068] The granulation liquid was prepared by first dissolving the amphiphilic Soluplus® in water using an Ultra-Turrax®. Apixaban was then finely dispersed in the resulting solution using an Ultra-Turrax®. The resulting suspension was stirred overnight at 50 °C using a magnetic stirrer. Embodiment 12 (according to the invention):

[0069] Tablets were produced as a dosage form according to the invention with the formulation given in Table 12 using the granules according to the invention (Phase I) which were manufactured using the process according to the invention. Table 12: ingredient Phase I Microcrystalline cellulose (Avicel PH 101) 175.74 mg Croscarmellose 8.00 mg Apixaban (free base) 5.00 mg Soluplus ®< (BASF, polyvinylcaprolactam polyvinyl acetate-polyethylene glycol graft copolymer with an average molecular weight of 90,000 to 140,000 g / mol) 0.26 mg Soluplus ®< (BASF, polyvinylcaprolactam polyvinyl acetate-polyethylene glycol graft copolymer with an average molecular weight of 90,000 to 140,000 g / mol) 10.00 mg Water (no longer contained in the final product) 90,00 Phase II Magnesium stearate 1.00 mg Final tablet weight (without film) 200.00 mg

[0070] The tablets were manufactured analogously to Example 1, whereby the powdered mixture was wet granulated using a solution / dispersion of apixaban in water / 0.26 mg Soluplus ®< as granulating liquid.

[0071] The granulation liquid was prepared by first dissolving the amphiphilic Soluplus® in water using an Ultra-Turrax®. Apixaban was then finely dispersed in the resulting solution using an Ultra-Turrax®. The resulting suspension was stirred overnight at 50 °C using a magnetic stirrer.

Claims

1. Method for producing a pharmaceutical granulate comprising as active substance apixaban or a salt thereof, comprising the steps of a) providing a solvent; b) combining the solvent with the active substance to obtain a granulating liquid; c) wet granulating a pulverulent material using the granulating liquid, wherein an amphiphilic substance is present in the solvent and the amphiphilic substance is a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or is selected from the group consisting of caprylocaproyl macrogol-8 glyceride, lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, oleoyl macrogol-6 glyceride, linoleoyl macrogol-6 glyceride and lauroyl macrogol-6 glyceride, and the active substance is present in the solvent in dissolved form, in dissolved and dispersed form, in dissolved and suspended form, or in dissolved, dispersed and suspended form.

2. Method according to Claim 1, characterized in that the solvent comprises water.

3. Method according to either of the preceding claims, characterized in that the active substance is apixaban.

4. Method according to any of Claims 1 to 3, characterized in that active substance and solvent are present in the granulating liquid in a weight ratio of 1:100 to 1:2500, preferably in a weight ratio of 1:200 to 1:1000, more preferably in a weight ratio of 1:200 to 1:600.

5. Method according to any of Claims 1 to 4, characterized in that active substance and amphiphilic substance are present in the granulating liquid in a weight ratio of 1:2 to 1:200, preferably in a weight ratio of 1:4 to 1:120, more preferably in a weight ratio of 1:4 to 1:80.

6. Method according to any of the preceding claims, characterized in that the solvent is combined with the active substance at a temperature above 30°C.

7. Method according to any of the preceding claims, characterized in that the method further comprises the step of d) drying the granulate.

8. Granulate obtainable by a method according to any of Claims 1 to 7.

9. Dosage form comprising a granulate according to Claim 8.