The present invention relates to stable transparent compositions in form of rapid release melt extrudates that contain selective partial adenosine A1 receptor agonists as active pharmaceutical ingredients, a polymeric compound as excipient and optionally a water-soluble sugar alcohol. This invention also relates to a solvent-free process of preparing said extrudates as well as the use of said extrudates in the production of rapid release preparations.

Poor soluble drugs in their crystalline form often show poor bioavailability. This might be managed by transforming the crystalline into an amorphous form. Melt extrusion is a method which enables such a conversion.

The principle of melt extrusion has been known for a very long time. In the extrusion process active ingredients and polymer are conveyed either simultaneously, without previous mixing, or as mixture, after previous mixing, in an extruder which has been heated so that the mixture becomes extrudable and the active ingredient does not undergo degradation. In contrast to conventional alternative solubilisation techniques such as co-precipitate methods, the use of solvents is not nec- essary. This is besides economic and safety aspects particularly important for drugs such as selective partial adenosine A1 receptor agonists whereof at least some show a very poor solubility in common solvents.

The production of preparations with rapid release of active ingredient by melt extrusion of hydroxy- propylcellulose (HPC) with a molecular weight of from 60 000 to 200 000 is described in WO 96/25149. Melt extrudates of nifedipine with low viscosity HPC with a preferred average molecular weight of 55 000 to 70 000 has been described by US 6,569,455.

The present invention relates to novel transparent rapid release compositions of selective partial adenosine A1 receptor agonists obtainable by extrusion of a melt comprising

a) at least one selective partial adenosine A1 receptor agonist, and

b) 50-99 % by weight of a polymeric compound, and

c) 0-30 % by weight of water-soluble sugar alcohols or mixtures thereof,

and subsequent shaping.

Selective partial adenosine A1 receptor agonists according to this invention are compounds of the formula (A)

in which

R ¹ represents (Ci-C4)-alkyl,

R ² represents (Ci-C4)-alkyl,

where (Ci-C4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, trifluoromethoxy, (C1-C4)- alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy and (Ci-C4)-alkylsulphonyl,

or

R ¹ and R ² each represent hydrogen

or

R ¹ and R ² together with the nitrogen atom to which they are attached form a 4- to 7-membered het- erocycle which may contain a further heteroatom from the group consisting of N, O and S, where the 4- to 7-membered heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (Ci- C4)-alkyl, trifluoromethyl and (Ci-C4)-alkoxy,

and the salts, solvates, and solvates of the salts thereof.

Depending on their structure, the compounds according to the invention may exist in stereoiso- meric forms (enantiomers, diastereomers). The invention therefore encompasses the enantiomers or diastereomers and the respective mixtures thereof. It is possible to isolate the stereoisomerical- ly homogeneous constituents from such mixtures of enantiomers and/or diastereomers in a known manner.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all the tautomeric forms.

Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also encompassed are salts which are not themselves suitable for pharmaceutical applications but can be used, for example, for isolation or purification of the compounds of the invention. Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoro- acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds of the invention also include salts of conventional bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts de- rived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzyla- mine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Designated as solvates in the context of the invention are those forms of the compounds accord- ing to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water. Solvates preferred in the context of the present invention are hydrates.

In the context of the present invention, unless specified otherwise, the substituents are defined as follows:

Alkyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms. Preferred examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

Cvcloalkyl in the context of the invention is a monocyclic saturated carbocycle having 3 to 7 ring carbon atoms. Preferred examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkoxy in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Preferred examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

Cvcloalkoxy in the context of the invention is a monocyclic saturated carbocycle which has 3 to 7 carbon atoms and is bonded via an oxygen atom. Preferred examples include: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.

Alkylsulphonyl in the context of the invention is a straight-chain or branched alkyl radical which has 1 to 4 carbon atoms and is attached via a sulphonyl group. Preferred examples include: me- thylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl and tert- butylsulphonyl. Heterocycle in the context of the invention is a saturated heterocycle which has a total of 4 to 7 ring atoms, contains one or two ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or optionally a ring nitrogen atom. Examples include: azetidinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpho- linyl, thiomorpholinyl and azepanyl. Preference is given to azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl.

In one embodiment of the invention the selective partial adenosine A1 receptor agonists are compounds of the formula (A), in which

R ¹ represents (Ci-C3)-alkyl,

R ² represents (Ci-C3)-alkyl,

where (Ci-C3)-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl,

or

R ¹ and R ² each represent hydrogen

or

R ¹ and R ² together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S, where the 4- to 6-membered heterocycle may be substituted by 1 or 2 substituents inde- pendently of one another selected from the group consisting of fluorine, trifluoromethoxyl,

(Ci-C4)-alkyl, trifluoromethoxy, methoxy and ethoxy,

and the salts, solvates, and solvates of the salts thereof.

In one embodiment of the invention the selective partial adenosine A1 receptor agonists are compounds of the formula (A), in which

R ¹ represents ethyl,

R ² represents ethyl,

or

R ¹ and R ² each represent hydrogen

or

R ¹ and R ² together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl ring,

where the azetidinyl ring may be substituted by a methoxy substituent,

and the salts, solvates, and solvates of the salts thereof.

In one embodiment of the invention the selective partial adenosine A1 receptor agonists are se- lected from the group consisting of 2-amino-6-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulphanyl)-4-[4^

pyridine-3,5-dicarbonitrile (known from WO 03/053441 ),

2-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]m

phenyl]pyridine-3,5-dicarbonitrile (known from WO 2010/086101 ),

2-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phen yl]-6-(3- methoxyazetidin-1-yl)pyridine-3,5-dicarbonitrile (known from WO 2010/086101 ),

2-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phen yl]-6-(pyrroli- din-1-yl)pyridine-3,5-dicarbonitrile(known from WO 2010/086101 ),

2-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phen yl]-6-(pip din-1-yl)pyridine-3,5-dicarbonitrile (known from WO 2010/086101 ),

and the salts, solvates, and solvates of the salts thereof.

Selective partial adenosine A1 receptor agonists which may be converted into the compositions according to the present invention are in particular selected from the following list:

2-Amino-6-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxyethoxy)pheny l]- pyridine-3,5-dicarbonitrile (known from WO 03/053441 and also known as Capadenoson)

2-({[2-(4-Chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxyethoxy)pheny l]-6-(pyrolidin- 1-yl)pyridine-3,5-dicarbonitrile (known from WO 2010/086101 and also known as Neladenoson)

The selective partial adenosine A1 receptor agonists are present in the compositions according to the invention in the range of 0.1 to 10 % by weight, preferably in the range of 1 to 7.5 %, further preferred in the range of 1.5 to 5 %.

The selective partial adenosine A1 receptor agonists are poorly soluble in water. When formulated as extrudate according to the invention a surprisingly higher relative bioavailability can be reached.

The compounds according to formula (A), in particular according to formula (I) and (II), act as partial adenosine A1 receptor agonists and may be used for the prevention and/or treatment of cardiovascular disorders like e.g. coronary heart disease, ischemic injury during acute coronary syndrome, angina pectoris, heart failure, worsening chronic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), myocardial infarction and atrial fibrillation

Examples of suitable polymeric compounds are hydroxypropylcellulose (HPC) with low or medium viscosity, hydroxypropyl methylcellulose acetate succinate (HPMC AS) or a polyvinyl caprolac- tam-polyvinyl acetate-polyethylene glycol graft co-polymer (marketed under the brand name Solup- lus ^® , see BASF Technical Information 03_090801 e-04 July 2010). Preferred for the present invention is HPC with low or medium viscosity.

The low viscosity hydroxypropylcellulose preferably has an average molecular weight of from

1 10 000 to 250 000, more preferably from 1 10 000 to 200 000, even more preferably from

1 1 1 000 to 150 000 and a viscosity in the range of 3.0 to 10.0 mPa · s (at 20 °C/2% aq.) (see e.g. Technical Data Sheet Nisso, HPC, TDS-01 , Version 1.7, 2015, Type SL and Type L).

The medium viscosity hydroxypropylcellulose preferably has a viscosity in the range of 150 to 400 mPa · s (at 20 °C/2% aq.) and an average molecular weight of about 620 000 g/mol (see e.g. Technical Data Sheet Nisso, HPC, TDS-01 , Version 1.7, 2015, Type M).

The molar degree of substitution refers to the average number of moles of propylene oxide per glucose unit in the cellulose.

The composition according to the invention comprises preferably 50 to 80 % or 60 to 90 %, more preferably 60 to 80 % and even more preferred 80 % by weight of HPC of low or medium viscosity.

Soluplus® has the following structure

Soluplus ^® has an average molecular weight of 90 000 to 140 000 g/mol.

The composition according to the invention comprises preferably 50 to 80 % or 60 to 95 %, more preferably 70 to 95 % and even more preferred 95 % by weight of Soluplus®.

Hydroxypropyl methylcellulose acetate succinate HPMC AS is a mixture of acetic acid and mono- succinic acid esters of hydroxypropyl methylcellulose as described in the monograph of the US Pharmacopeia (USP 39-NF 34, 2016). According to the invention different types may be used, e.g. Affinisol™ products from Dow (grades 716G, 912G and 126G) or AQOAT ^® products from ShinEtsu (grades AS-LG/LF, AS-MG/MF, AS_HG/HF).

Examples of suitable sugar alcohols are mannitol, xylitol, sorbitol, adonitol, dulcitol and generally pentitols and hexitols. Preferred for the present invention is maltitol.

The composition according to the invention may comprise water-soluble sugar alcohol or mixtures thereof. The composition comprises preferably 5-25 %, more preferably 10-20 % and even more preferred 15 % by weight of a water-soluble sugar alcohol or mixtures thereof.

In one embodiment the present invention relates to novel transparent rapid release compositions of selective partial adenosine A1 receptor agonists obtainable by extrusion of a melt comprising a) at least one selective artial adenosine A1 receptor agonist of the formula (A)

in which

R ¹ represents (Ci-C4)-alkyl,

R ² represents (Ci-C4)-alkyl,

where (Ci-C4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, trifluorometh- oxy, (Ci-C4)-alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy and (Ci-C4)-alkylsulphonyl, or

R ¹ and R ² each represent hydrogen

or R ¹ and R ² together with the nitrogen atom to which they are attached form a 4- to 7- membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,

where the 4- to 7-membered heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, trifluorome- thyl, (Ci-C4)-alkyl, trifluoromethyl and (Ci-C4)-alkoxy,

and the salts, solvates, and solvates of the salts thereof,

and

b) 50-99 % by weight of a polymeric compound selected from the group consisting of hydroxy- propylcellulose (HPC) with low or medium viscosity, hydroxypropyl methylcellulose acetate succinate (HPMC AS) or a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer,

where the low viscosity HPC has a viscosity in the range of 3.0 to 10.0 mPa · s (at 20 °C/2% aq.) and the medium viscosity HPC has a viscosity in the range of 150 to 400 mPa · s (at 20 °C/2% aq.),

and

c) 0-30 % by weight of water-soluble sugar alcohols or mixtures thereof,

and subsequent shaping.

In another embodiment the present invention relates to novel transparent rapid release compositions of selective partial adenosine A1 receptor agonists obtainable by extrusion of a melt comprising

a) at least one selective partial adenosine A1 receptor agonist of the formula (A)

in which

R ¹ represents (Ci-C4)-alkyl,

R ² represents (Ci-C4)-alkyl, where (Ci-C4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, trifluorometh- oxy, (Ci-C4)-alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy and (Ci-C4)-alkylsulphonyl, or

R ¹ and R ² each represent hydrogen

or

R ¹ and R ² together with the nitrogen atom to which they are attached form a 4- to 7- membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,

where the 4- to 7-membered heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (Ci-C4)-alkyl, trifluoromethyl and (Ci-C4)-alkoxy,

and the salts, solvates, and solvates of the salts thereof,

and

b) 50-99 % by weight of a polymeric compound selected from the group consisting of hydroxy- propylcellulose (HPC) with low or medium viscosity, hydroxypropyl methylcellulose acetate succinate (HPMC AS) or a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer,

where the low viscosity HPC has a viscosity in the range of 3.0 to 10.0 mPa · s (at 20 °C/2% aq.) and the medium viscosity HPC has a viscosity in the range of 150 to 400 mPa · s (at 20 °C/2% aq.),

and

c) 0-30 % by weight of water-soluble sugar alcohols selected from the group consisting of mannitol, xylitol, sorbitol, adonitol, dulcitol, pentitols and hexitols or mixtures thereof, and subsequent shaping.

The invention furthermore relates to a solvent-free process for producing such compositions (cf. US 6,569,455). By use of the described excipients and application of the described melt-extrusion process stable fast-release selective partial adenosine A1 receptor agonist formulations with improved bioavailability can be manufactured.

Transparent melt extrudates with the desired fast release and high stability can be obtained in a simple manner with the specifically selected polymer hydroxypropylcellulose of low or medium viscosity with an average molecular weight from 1 10 000 to 300 000 or about 620 000 g/mol, respectively, and with a molecular degree of substitution of at least 3 in an amount of 50-99 % by weight, preferably 50-80 % or 60-90 %, more preferably 60-80 % and even more preferred 80 % by weight, based on the active ingredient/polymer mixture in conjunction with selective partial adenosine A1 receptor agonists and, where appropriate, excipients.

The present application also relates to preparations produced with the use of the extrudates of the invention. Fast-release extrudates or preparations mean for the purposes of the invention those which release 80 % of the active ingredient(s) within 60 min in the USP paddle method (see USP 39, Chapter 724 - Drug Release). The extrudates or preparations of the invention display very rapid release and show significant super-saturation. They are therefore particularly well suited for fast reaching of high plasma concentrations of active pharmaceutical ingredient. The release of active ingredient is influenced, for example, by the concentration of active ingredient in the final product or by extrusion process parameters such as the screw geometry, the extrusion rate, the extrusion temperature, the diameter and surface area of the extrudate etc. The release rate is influenced in particular by the particle size of the extrudate. In single-unit dosage form such as, for example, tablets, the release is influenced in particular by the content of disintegrant in the final formulation.

It is also possible during the melt extrusion process or during further processing, for example tab- leting, to use other conventional excipients which are conventional in pharmacy in the production of preparations and are known from the literature, such as, for example, magnesium stearate or masking flavours. None of these excipients is, however, necessary in order to achieve essentially the desired fast release of the drug.

In a preferred embodiment, the extrudate or the preparation is administered orally. For this purpose, in one embodiment, the extrudate of the invention is comminuted, for example, ground to an average particle diameter of less than 1 mm, sieved using 600 μηη sieve mm and packed e.g. as sachet.

In a further embodiment, the extrudate of the invention is, where appropriate in comminuted form, mixed with a disintegrant and, where appropriate, further excipients and processed to a single-unit dosage form. Disintegrants are substances which ensure rapid disintegration of dosage forms in aqueous solution, such as, for example, crosslinked poylvinylpyrrolidone (e.g. polyvinylpolypyrrol- idone, PVPP, or crospovidone). In this case it is preferred to use large amounts of disintegrant, that is to say more than 0.1 part by weight of disintegrant per 1 part of extrudate (active ingredi- ent(s), HPC and optionally water-soluble sugar alcohol).

Single-unit dosage forms mean preparations which are administered as single dose, for example tablets, coated tablets or capsules.

In the present process, a mixture of at least one selective partial adenosine A1 receptor agonists and a polymeric compound an amount of at least 50 % by weight and optionally a water-soluble sugar alcohol or mixtures thereof is produced, and the mixture is passed through an extruder which has at the place where the product enters a temperature of from 20 to 40°C, and at the exit die or dies a temperature of <225°C, where the exit dies have a diameter of from 0.5 to 5 mm, preferably from 1 to 3 mm, and the extruded strands are comminuted after their emergence. The residence time of the mixture in the extruder depends on technical aspects of the process and may vary to a large degree. It is generally less than 60 min, preferably less than 30 min.

The ingredients can be mixed before entry into the extruder or inside the extruder. Premixing, that is to say mixing before entry, is preferred, inter alia for reasons of the content uniformity.

The extrudates obtained in this way may be formulated as granulates by adding common pharmaceutical excipients such as flavours, glidants and other processing agents, if needed. The ex- trudates may also be packed into sachets or sticks. It is also possible to process the extrudates into immediate-release tablets or orally-dispersible tablets or chewable tablets.

The invention is explained further by means of the following examples.

Examples

Measurement of the active ingredient release by the USP paddle method

The release of the above mentioned selective partial adenosine A1 receptor agonists from the extrudates, tablets, sachets is measured by the USP XXII paddle method. Stirrer speed 75 rpm, release medium acetate buffer pH 4.5 or phosphate buffer pH 6.8 (0.9 L) with small amounts of sol- ubilizers [for example <0.5 (w/v) sodium lauryl sulphate], temperature 37 °C. All the examples release > 50 % of the active ingredient within 60 min, mostly even >75 % in 60 min.

Example 1

1 part by weight of compound of formula (I) is mixed with low-viscosity HPC (average MW about 11 1 000 to 150 000 g/mol), so that an average amount of HPC of 50-80 %, preferably 80 %, is included in the mixture. Maltitol is added with an average amount of 0-30 %, preferably 15 %. The mixture is processed in a twin screw extruder with an exit die having a diameter of 1 mm. The mate- rial is extruded at a die temperature of 178 °C. The transparent extrudates are comminuted, and the fraction (< 250 μηη) is mixed with common pharmaceutical excipients to gain oral dosage forms.

Example 2

Analogous to example 1 but the mixture is formulated as granulate by adding common pharmaceutical excipients such as flavours, glidants and other processing agents, if needed.

Example 3

Analogous to example 2 but the mixture is packed into sachets.

Example 4

Analogous to example 2 but the mixture is packed into sticks. Example 5

Analogous to example 1 but the mixture is processed into immediate-release tablets.

Example 6

Analogous to example 1 but the mixture is processed into orally-dispersible tablets.

Example 7

Analogous to example 1 but the mixture is processed into chewable tablets.

Example 8

0.5 g of compound of formula (II) is mixed with 8 g medium-viscosity HPC (average MW about 620 000 g/mol, 150 to 400 mPa · s at 20 °C/2% aq.), and 1.5 g Maltitol in a mixer for 10 min. The powder blend is processed in a twin screw extruder with an exit die having a diameter of 1 mm. The material is extruded for 7 to 20 min at a die temperature of 160 to 175°C. The transparent ex- trudates are comminuted and the fraction (< 600 μηη) was further used. Yield after extrusion: 5.8 to 7.2 g, yield after milling and sieving: 4.7 to 5.9 g. For characterisation X-ray analysis to confirm the amorphous state of the active, in-vitro dissolution testing and in-vivo PK-analysis in rats was conducted.

Example 9

0.5 g of compound of formula (II) is mixed with Soluplus ^® HS 15 (Supplier: BASF) in a mixer for 10 min. The powder blend is processed in a twin screw extruder with an exit die having a diameter of 1 mm. The material is extruded for 7 to 20 min at a die temperature of 160 to 175°C. The trans- parent extrudates are comminuted and the fraction (< 600 μηη) was further used. Yield after extrusion: 5.8 to 7.2 g, yield after milling and sieving: 4.7 to 5.9 g. For characterisation X-ray analysis to confirm the amorphous state of the active, in-vitro dissolution testing and in-vivo PK-analysis in rats was conducted.

Example 10

0.5 g of compound of formula (II) is mixed with Hydroxypropylmethylcellulose acetate succinate (HPMC AS) in a mixer for 10min. The powder blend is processed in a twin screw extruder with an exit die having a diameter of 1 mm. The material is extruded for 7 to 20 min at a die temperature of 160 to 175°C. The transparent extrudates are comminuted and the fraction (< 600 μηη) was further used. Yield after extrusion: 5.8 to 7.2 g, yield after milling and sieving: 4.7 to 5.9 g. For char- acterisation X-ray analysis to confirm the amorphous state of the active, in-vitro dissolution testing and in-vivo PK-analysis in rats was conducted.

Example 1 1

The in-vivo plasma pharmacokinetics of the compound of formula (II) were investigated in fasted male Wistar rats after single peroral administration of two extrudates (selected from the above ex- amples: Soluplus and HPC Type M) compared to a solution of a prodrug of the compound of formula (II).

The extrudate powder after milling was dispersed in water and administered in 5 mL/kg to the animals. Since the compound of formula (II) has a very low solubility in water for the purpose of comparison with the formulations according to the invention the hydrochloride salt of the prodrug (i.e. 2-{4-[2-({[2-(4-chlorophenyl)-1 ,3-tN

pyridin-4-yl]phenoxy}ethyl L-alanyl-L-alaninate hydrochloride) is used to obtain a solution. This prodrug of the compound of formula (II) was dissolved in a PEG-400/EtOH-based formulation and dosed in 5 mL/kg to the animals.

The administered doses are related to the compound of formula (II). Plasma samples were collected at predefined time points up to 96 h post dosing. The calculated pharmacokinetic parameters refer to the compound of formula (II) (analyte) and are summarized in the table below.

Example 9 8

Dose [mg/kg] 2.41 14.0 14.0

10% EtOH

Polymer: HPC, Type M Formulation 40% PEG400 Polymer: Soluplus

Additive: Maltitol, 15 % 50% demin. water

Appl. Vol. [mL/kg] 5 5 10

Animals per time point 3 4 4

AUC Mg · h/L 1910 2800 5780

AUCnorm kg · h/L 0.794 0.200 0.413 tlast h 96.0 96.0 96.0

6

t½ h 22.9 18.2 17.5

Rpoints 3 3-4 3-4

The exposure of the compound of formula (II) in terms of AU Cnorm was 0.794 kg · h/L when administered as prodrug in solution. The exposure of the Soluplus extrudate was 0.200 kg · h/L and of the H PC Type M extrudate was 0.413 kg · h/L. The relative bioavailability (F _re i, prodrug solution set to 100 %) was about 25 % for the Soluplus extrudate and about 52 % for the H PC Type M extrudate. Since the compound of formula (II) has a very low solubility in water it is thus surprising that such a high relative bioavailability can be reached using the extrudate formulations according to the invention.

The maximum concentration of the compound of formula (II) in rat plasma was reached 3 h (tmax) after administration of the three formulations. The dose-normalized C _ma x was 0.0716 kg/L after dosing as prodrug in solution and was 0.0180 kg/L for the Soluplus extrudate and 0.0366 kg/L for the H PC Type M extrudate. The elimination half-life of the compound of formula (II) was long for the three tested formulations and ranged between 17.5 h and 22.9 h determined in the interval up to 96 h post dosing.