WO2016102423A1

WO2016102423A1 - Composition comprising ivabradine in a dissolved form

Info

Publication number: WO2016102423A1
Application number: PCT/EP2015/080716
Authority: WO
Inventors: Wolfgang Albrecht; Jens Geier; Frank Lehmann
Original assignee: Ratiopharm Gmbh
Priority date: 2014-12-22
Filing date: 2015-12-21
Publication date: 2016-06-30

Abstract

The present invention relates to a composition comprising ivabradine in a dissolved form and oral dosage forms comprising said composition. The invention further relates to a process for producing the composition comprising ivabradine in a dissolved form and to the corresponding process of producing an oral dosage form containing the composition of the invention. Further, the invention relates to a method for treating cardiac diseases, preferably angina pectoris, comprising administering said composition. Finally, the invention relates to the use of a saturated ivabradine solution for the preparation of a solid oral dosage form.

Description

position Comprising Ivabradine in a Dissolved Form

Background of the invention The present invention relates to a composition comprising ivabradine in dissolved form and oral dosage forms comprising said composition. The invention further relates to a process for producing the composition comprising ivabradine in a dissolved form and to the corresponding process of producing an oral dosage form containing the composition of the invention. Further, the invention relates to a method for treating cardiac diseases, preferably angina pectoris, comprismg administering said composition. Finally, the invention relates to the use of a saturated ivabradine solution for the preparation of a solid oral dosage form.

Ivabradine is an active pharmaceutical ingredient whose effect is reported to be based on the selective and specific inhibition of the I_f current. By inhibiting the I_f current controlling the spontaneous diastolic depolarisation in the sino-atrial node, the heart rate or cardiac frequency can be reduced. The cardiac effect is reported to be specific to the sinu-atrial node and does not affect for example the myocardial contractility, haemodynamics and blood pressure. Due to the reduction of the heart rate by some beats per minute the oxygen demand of the heart is reduced, which is advantageous in cases of attacks of angina pectoris. For this purpose ivabradine is indicated for the symptomatic treatment of angina pectoris, in particular for patients who cannot take beta-blockers, for example due to an intolerance or a contraindication.

In the context of this invention, the term "ivabradine" refers to 3-{3-[ {[(7S)-3,4- dimethoxybicyclo[4.2.0]octa-l,3,5-trien-7-yl]methyl}methylamino]propyl}-7,8- dimethoxy - l ,3,4,5-tetrahydro-2H-3-benzazepin-2-one according to Formula (1).

Formula (1) Generally, the term "ivabradine" refers to ivabradine in form of the free base or in form of a pharmaceutically acceptable salt. In a particularly preferred embodiment ivabradine is present in the form of the HC1 salt according to Formula (la)

Formula (la)

Synthesis pathways for ivabradine and its use for the prevention and treatment of cardiovascular ailments have been described in EP 0 534 859 Al. Ivabradine hydrochloride is reported to have several polymorphic forms. EP 1 589 005 Bl, for example, discloses ivabradine hydrochloride in form of the a-polymorph.

Further, EP 1 695 965 B9 discloses a polymorph of ivabradine hydrochloride, the so-called β polymorph, and a method to prepare said specific polymorph. Ivabradine hydrochloride in form of its β polymorph is assumed to be used in the corresponding market product Procolaran^®. For several reasons, e.g. for regulatory reasons, it is desirable to provide on the one hand ivabradine hydrochloride in a form which is not encompassed by the scope of EP 1 695 965 B9.

Further polymorphs and the amorphous form are disclosed in WO 2008/065681, WO 2008/146308 and WO 2007/042656 / WO 2007/042657.

Furthermore, WO 2013/150544 A2 relates to solid dispersions of ivabradine hydrochloride together with a pharmaceutically acceptable carrier and to a process for the preparation these solid dispersions, in which the active pharmaceutical ingredient is present in a preferably amorphous form. However, it can be seen that the amorphous form easily converts to an at least partially crystalline form. With regard to regulatory reasons such a behaviour is disadvantageous and a homogenous form of the active pharmaceutical ingredient is desirable.

As mentioned above, ivabradine hydrochloride can be present in different polymorphs. However, it turned out that several of these polymorphic forms are not stable. As can be seen from Table 1 several polymorphic forms and even the amorphous form of ivabradine hydrochloride tend to convert into other polymorphs, for example under the influence of heat or in a moist environment.

Table 1: Results of stability test of ivabradine hydrochloride (IVA/HC1) forms I, , β and δ with Tl=33days and T2=l lmonths and ivabradine hydrochloride (IVA/HC1 amorphous with Tl=57days and T2=9months

A conversion of polymorphic forms can be unfavourable in pharmaceutical dosage forms such as tablets, often resulting in different dissolution and pharmacokinetic properties. As a result, the concentration of the active agent might be undesirably unpredictable. Consequently, active agents having different interchangeable polymorphs may lead to regulatory and commercial disadvantages and since they very often do not fulfil the requirements of the corresponding regulation authorities such as the FDA and EMEA.

Hence, it was an object of the present invention to overcome the above drawbacks.

In particular, it was an object of the present invention to provide ivabradine in a form which does not require a specific temperature control during storage or when used in climate zones III and IV. Further, a form of ivabradine hydrochloride should be provided that shows advantageous dissolution and pharmacokinetic properties, in particular when used after storage or in in climate zones III and IV.

Moreover, as mentioned above it was an object to provide ivabradine hydrochloride in a form not being protected by the scope of EP 1 695 965 B9.

All the above-mentioned objectives should preferably be solved for a dosage form designed for immediate release ("IR") or for modified release ("MR"). Summary of the Invention

According to the present invention, the above objectives can be achieved by a pharmaceutical composition comprising dissolved ivabradine, organic solvent with a specific boiling point and carrier. In the composition of the present invention ivabradine is present in a dissolved form in an organic solvent with a specific boiling point and may adhere to said carrier or is preferably adsorbed on said carrier in dissolved form. The composition can advantageously be processed into oral dosage forms and can be used under hot environmental conditions without iindergoing any solid state changes.

Thus, the subject of the invention is a pharmaceutical composition, preferably a pharmaceutical composition having a solid appearance, comprising dissolved ivabradine, (b) organic solvent with a boiling point of 110 to 350°C at 1013 mbar and

(c) solid carrier.

Atmospheric pressure, 1013 mbar and 760 mm Hg are equivalent values and refer to standard pressure.

A further subject of the present invention is an oral dosage form comprising the composition of the invention and optionally further pharmaceutical excipient(s).

Another subject of the present invention is a method of producing the composition according to the invention comprising the steps of i) dissolving ivabradine (a) in organic solvent (b) with a boiling point of 110 to 350°C, wherein the boiling point is measured at 1013 mbar ii) mixing solid carrier (c) and solution of step i)

iii) optionally milling and/or sieving the mixture of step ii).

Further, the subject of the present invention relates to a process for producing an oral dosage form comprising the steps of i) dissolving ivabradine (a) in organic solvent (b) with a boiling point of 110 to 350°C, wherein the boiling point is measured at 1013 mbar ii) mixing solid carrier (c) and the solution of step i)

iii) optionally milling and/or sieving the mixture of step ii)

iv) optionally adding further excipient to the mixture of step iii) v) processing the mixture of step i), step ii) or step iii) into an oral dosage form

Finally, a subject of the present invention relates to the use of saturated ivabradine solution for producing a solid oral dosage form wherein said dosage form is free of any crystalline polymorph of ivabradine.

The above-illustrated subjects of the present invention are alternative solutions to the above-outlined problems. Detailed Description of the Invention

The present invention concerns a pharmaceutical composition which is a mixture of a solid state carrier and ivabradine in dissolved state. Preferably, the physical appearance of the entire composition is solid at 25°C. The same applies to the dosage form of the present invention.

The organic solvent (b) has a boiling point of about 110°C to about 350°C, wherein the boiling point is measured at 1013 mbar. However, this does not imply that the ivabradine has to be dissolved at 1013 mbar in the organic solvent (b).

The term "ivabradine" as used in the present application preferably can refer to ivabradine according to the above Formula (1) or ivabradine hydrochloride according to the above Formula (la). Ivabradine hydrochloride according to Formula (la) is particularly preferred. Alternatively, it can refer to pharmaceutically acceptable solvates, hydrates and mixtures thereof.

In case the weight of ivabradine is mentioned in the present invention, this refers to the weight of ivabradine in form of the free base. Thus, for example, 5.00 mg of ivabradine in its free form corresponds to 5.39 mg of ivabradine hydrochloride.

In a particularly preferred embodiment the composition of the present invention as well as the oral dosage form of the present invention comprise ivabradine as the sole pharmaceutical active agent.

In an alternative embodiment the composition of the present invention as well as the oral dosage form of the present invention can comprise ivabradine in combination with further pharmaceutical active agent(s). The composition of the present invention preferably contains "dissolved ivabradine", i.e. ivabradine in a dissolved form.

The term "dissolved ivabradine" can be used in the context of this invention to designate the above compound in which the components (atoms, ions or molecules) do not exhibit a periodic arrangement over a great range (= long-range order) as usually known from crystalline substances. Consequently, the present ivabradine for example does not show any clear peaks determined by means of X- ray diffraction. The present ivabradine components (atoms, ions or molecules, preferably ions) each are preferably surrounded by a solvate shell. This solvate shell can be composed of several layers of solvent molecules wherein the molecules of the various layers of the solvate shell interact more with the core molecule the closer they are to said core molecule. Solvated molecules can preferably be regarded as a flexible entity whose solvate shell is in interaction with solvent molecules.

In a preferred embodiment dissolved ivabradine, e.g. the dissolved ivabradine hydrochloride, can be regarded as non-solid ivabradine or in other words ivabradine in a non-solid form.

In a preferred embodiment of the composition the organic solvent (b) has a melting point between -80°C and 25°C, preferably between -75°C and 10°C, more preferably between -72°C and 5°C, especially between -70° and -5°C at 1013 mbar. Thus, the organic solvent used in the present invention is liquid at room temperature (25°C).

It is further preferred that the organic solvent (b) has a boiling point of about 110°C to about 350°C, preferably at 1013 mbar. Further preferred, the organic solvent can have a boiling point of at least 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C or 190°C. Further preferred, the organic solvent can have a boiling point of up to 345°C, 340°C, 335°C, 330°C, 325°C, 320°C, 315°C or 310°C. All possible combinations (e.g. 170 to 340°C) of the above lower and upper limits are also preferred. Preferably, the temperature is determined at 1013 mbar. In this application a "boiling point of about 110°C to about 350°C" also encompasses those organic solvents (b) that undergo decomposition in said temperature range. Further, the boiling point is not related to a single temperature but can also refer to a temperature interval, for example when a mixture of organic solvents is used.

Preferably, the boiling point is determined according to Pharm. Eur. 6.0, Chapter 2.2.12.

In a further embodiment of the invention the organic solvent (b) has a density of 0.95 to 1.30 g/ml. It is further preferred that the organic solvent (b) has a density of 1.00 to 1.20 g/ml at 25°C, even more preferably 1.02 to 1.17 g/ml, especially 1.03 to 1.13 g/ml. The density can be determined the following formula: m

^{P =} V m = mass of the solvent

V— volume of the solvent

In a further embodiment of the invention the organic solvent (b) has a vapour pressure of less than 10 hPa or mbar at 20°C, preferably less than 1 hPa or mbar at 20°C.

The vapour pressure is the vapour exerted by a vapour P in a thermodynamic equilibrium with its liquid phase at a given temperature in a closed system. According to the Antoine equation the estimated vapour pressures can be calculated.

B

logP - A - -— - 6 C + T wherein

A, B and C are substance-specific coefficients (i.e. constants or parameters) and T is the temperature of the liquid.

It is preferred that the organic solvent (b) comprises one to three hydroxy groups, preferably two or three hydroxy groups, especially two hydroxy groups.

For example, organic solvent (b) can be polyethylene glycols such as tetraethylene glycol and pentaethylene glycol, polyethyleneglycol ether such as diethyleneglycol monoethylether, glycerol, propylene glycol such as 1 ,2-propylene glycol, alcohol such butyl alcohol and pentyl alcohol, alkyl diols such as 2,3-butanediol, triols such as 1 ,2,6-hexantriol, dimethylisosorbid, Glycofurol (tetrahydrofufuryl polyethylene glycol), polydimethyl siloxane and mixtures thereof. Especially preferred are 1,2-propylene glycol, 2,3-butanediol, glycerol, dimethylisosorbid, Glycofurol, polyethylene glycol and diethyleneglycol monoethylether. 1 ,2- propylene glycol, 2,3-butanediol, dimethylisosorbid and polyethylene glycol are more preferred. Particularly preferred is 1,2-propylene glycol. Alternatively particularly preferred is 2,3-butanediol Alternatively particularly preferred is polyethylene glycol, in particular PEG 200.

The composition of the present invention can preferably have a weight ratio of dissolved ivabradine (a) to organic solvent (b) of 1 : 1 to 1 :40, preferably 1 :1 to 1 : 15, more preferably of 1 : 1 to 1 : 10, even more preferably of 1 : 1 to 1 :7, most preferably of 1 : 1 to 1 :5. It turned out that with the above ratio it can be particularly ensured that the complete amount of ivabradine remains in the dissolved state and does not precipitate as a solid (crystalline) substance. The present composition further comprises a carrier (c). The carrier is preferably solid, wherein "solid" refers to the appearance at 25°C. The term "carrier (c)" may refer to a single carrier (c) or a mixture of more than one carrier (c). The carrier (c) can be regarded as a substance to which dissolved ivabradine (a) and organic solvent (b) can be adhered/ adsorbed, wherein it is ensured that the ivabradine maintains its dissolved state.

Further, due to the solid carrier (c) the physical composition can be provided in a state suitable for further processing, such as filling into a capsule. Alternatively, the physical composition can be provided for a compression process, for example for a tableting process.

In a preferred embodiment the present composition can have a Carr's index of 5 to 21. In an alternative more preferred embodiment the present composition can have a Carr's index of 12 to 16. In an alternative even more preferred embodiment the present composition can have a Carr's index of 5 to 15. The Carr's index (%) can be determined by the following equation

Carr's index{%) = ^pped density-poured density _{χ y QQ}

v ' tapped denisty The tapped density and poured density is determined according Pharm. Eur. 4.0, 2.9.15. The tapped density is determined after 1250 stamps (V₁₂₅o).

In a preferred embodiment the composition of the invention can comprise ivabradine (a) and carrier (c), wherein the weight ratio of dissolved ivabradine (a) to carrier (c) can be from 1 : 1 to 1 :50, preferably from 1 : 1 to 1 :20, more preferably from 1 : 1 to 1 :15, even more preferably from 1 : 1 to 1 : 10 and particularly from 1 :1 to 1:7.

Generally, the carrier (c) can be a non-brittle or brittle substance.

Pharmaceutical excipients, such as carriers, can generally be classified with regard to the change in the shape of the particles under compression pressure (compaction): plastic excipients are characterised by plastic deformation, whereas when compressive force is exerted on brittle substances, the particles tend to break into smaller particles. Brittle behaviour on the part of the substrate can be quantified by the increase in the surface area in a moulding. In the art, it is customary to classify the brittleness in terms of the "yield pressure". According to a simple classification, the values for the "yield pressure" are low for plastic substances but high in the case of friable substances (Duberg, M., Nystrom, C, 1982, "Studies on direct compression of tablets VI. Evaluation of methods for the estimation of particle fragmentation during compaction", Acta Pharm. Suec. 19, 421-436; Humbert-Droz P., Mordier D., Doelker E., "Methode rapide de determination du comportement a la compression pour des etudes de preformulation.", Pharm. Acta Helv., 57, 136-143 (1982)). The "yield pressure" describes the pressure that has to be reached for the excipient (i.e. preferably the vehicle) to start flowing plastically.

The "yield pressure" is preferably calculated by using the reciprocal of the gradient of the Heckel plot, as described in York, P., Drug Dev. Ind. Pharm. 18, 677 (1992). The measurement in this case is preferably made at 25°C and at a deformation rate of 0.1 mm/s.

In the context of the present invention, an excipient (especially a carrier) is deemed to be a non-brittle excipient when it has a yield pressure of not more than 120 MPa, preferably not more than 100 MPa, in particular 5 to 80 MPa. An excipient is usually described as a brittle excipient when it has a yield pressure of more than 80 MPa, preferably more than 100 MPa, particularly preferably more than 120 MPa, especially more than 150 MPa. Brittle excipients may exhibit a yield pressure of up to 300 MPa or up to 400 MPa or even up to 500 MPa.

Examples of non-brittle excipients (vehicles) are mannitol or starch.

Examples of brittle excipients (vehicles) are silicates or aluminosilicates, preferably magnesium aluminosilicates.

In a particularly preferred embodiment, brittle substances are used as a carrier (c) in the oral dosage form of the present invention. It is further preferred that the carrier (c) is a water insoluble substance. A water insoluble substance generally is a pharmaceutical excipient as specified in the European Pharmacopoeia, with a water solubility of less than 33 mg/ml, measured at 25°C. Preferably, water insoluble substance has a solubility of 10 mg/ml or less, more preferably 5 mg/ml or less, especially less than 0.1 mg/ml, which means practically insoluble (determined according to column elution method pursuant to EU Directive 67/548/EEC, Appendix V, Chapt. A6).

In a preferred embodiment of the invention the carrier can be an organic polymer or an inorganic substance.

In a preferred alternative embodiment of the invention the carrier (c) can preferably be an organic polymer. In addition, the carrier (c) can also include substances which behave like polymers. Examples of these substances are fats and waxes. Furthermore, the carrier (c) can also include solid, non-polymeric compounds, which preferably can contain polar side groups. Examples of these compounds are sugar alcohols or disaccharides.

In a preferred embodiment the carrier (c) can be a polymer. The polymer to be used for the preparation of the pharmaceutical composition preferably may have a glass transition temperature (Tg) of more than 45°C, more preferably of 50°C to 150°C, in particular of 55°C to 120°C. A respective Tg can be important for achieving the desired properties of the resulting dosage form. In the present invention the term "glass transition temperature" (Tg) describes the temperature at which amorphous or partially crystalline polymers change from the solid state to the liquid state. In the process a distinct change in physical parameters, e.g. hardness and elasticity, occurs. Beneath the Tg a polymer is usually glassy and hard, whereas above the Tg it changes into a rubber-like to viscous state. The glass transition temperature is determined in the context of this invention 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 l-20°C/min, preferably 10°C/min, and at a cooling rate of 5°C to 50°C/min, preferably 50°C/min.

In general, the organic polymer to be used as carrier (c) preferably can have a weight- average molecular weight of 1,000 to 500,000 g/mol, more preferably from 1,500 to 100,000 g/mol and particularly from 2,000 to 50,000 g/mol. The weight- average molecular weight is preferably determined by means of gel permeation chromatography.

In the present invention, hydrophilic polymers can preferably be used as carrier (c). The term "hydrophilic polymers" generally refers to polymers which possess hydrophilic groups. Examples of suitable hydrophilic groups can be hydroxy, sulfonate, carboxylate and quaternary ammonium groups.

The carrier (c) may for example comprise the following polymers: microcrystalline cellulose, polysaccharides, such as hydroxypropyl methyl cellulose (HPMC), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), polyvinyl alcohol, polyvinylpyrrolidone and mixtures thereof. Alternatively, also a silicone, preferably further mixed with silicon dioxide such as simethicone, can be used as carrier (c).

In a more preferred embodiment of the invention the carrier (c) can be an inorganic substance. An inorganic substance can preferably be regarded as a compound that does not contain a hydrocarbon group. It is further preferred that the carrier (c) can be a phosphate or a silicate, preferably a silicate, more preferably an aluminosilicate.

Examples for inorganic substances suitable to be used as carriers are phosphates, such as dicalcium phosphate, amorphous silica such as aerosil and silica gel,, clay minerals, such as kaolinite, bentonite and montmorillonite, kieselguhr (celite), zeolites, mesoporous silica, such as Aeroperl^® 300, MSU-G, MSU-F, MCM-41 , MCM-48, SBA-15 and SBA-16 and magnesium aluminosilicates, such as Al₂0₃-MgO 1.7Si0₂-xH₂0 (Neusilin) and aluminosilicates such as Al-MCM-41 or mixtures thereof.

Further, active coal (i.e. activated carbon) can be preferably used as carrier (c).

In a preferred embodiment the carrier (c), in particular the inorganic carrier (c), has a specific surface area of 50 to 450 m g, more preferably 75 to 400 m /g, in particular 100 to 300 m²/g. The specific surface area preferably is determined by gas adsorption according to Ph. Eur., 6^th edition, Chapter 2.9.26. For this purpose, an ASAP^® 2020 (Micrometrics) and an Outgasing' temperature of 40°C is used. It has surprisingly been found that the above-mentioned specific surface area might be beneficial for achieving the above-mentioned objects (e.g. stabilisation of the dissolved state of ivabradine hydrochloride).

In a preferred embodiment the carrier (c) is selected from simethicone, activated carbon, microcrystalline cellulose, starch, polysaccharides, sugar alcohols, phosphates, silicon dioxides, clay minerals, kieselguhr, zeolites, mesoporous silica and magnesium aluminosilicates or mixtures thereof.

In a more preferred embodiment the carrier (c) is selected from simethicone, active coal, micro crystalline cellulose, phosphates, silicon dioxides, clay minerals, kieselguhr, zeolites, mesoporous silica and magnesium aluminosilicates or mixtures thereof.

Most preferred as carrier (c) are magnesium silicates, especially Al₂0₃-Mg01.7Si0₂-xH₂0.

Alternatively most preferred as carrier (c) is silica, in particular mesoporous silica.

It is further preferred that the mesoporous silica is in form of pearl-like mesoporous granulates. The granulates can preferably have a mean particle size D50 of 5 to 250 μηι, more preferably 10 to 100 μηι, even more preferably 15 to 80 μηι, in particular 20 to 50 μηι.

Preferably, the mesoporous silica has a specific surface area of 250 to 350 m²/g, m particular, 280 to 320 m /g. Preferably, the volume of the mesoporous silica is 1.0 to 2.5 ml/g, more preferably 1.4 to 1.8 ml/g.

The mean particle size can refer to the D₅₀ of the particle size distribution. The average particle size can be determined by means of laser diffractometry. In particular, a Malvern Instruments Mastersizer 2000 can be used to determine the size (preferably wet measurement with ultrasound 60 sec, 2,000 rpm, preferably dispersed in sunflower oil, the evaluation being performed according to Particle RI set to 1.520 and Absorption of 2). In a particularly preferred embodiment Aeroperl 300 is used.

In an alternative particularly preferred embodiment Neusilin is used.

In a preferred embodiment the composition of the present invention can preferably comprise the following amounts of components:

1 to 25 mg ivabradine HC1, preferably 2.5 to 10 mg ivabradine, particularly 5 or 7.5 mg ivabradine, 1 to 350 mg organic solvent, preferably 11.5 to 50 mg organic solvent, particularly 4.5 to 35 mg organic solvent,

1 to 400 mg carrier, preferably 15 to 60 mg carrier, particularly 30 to 45 mg carrier.

In an alternatively preferred embodiment the composition of the present invention can preferably comprise the following amounts of components:

1 to 25 mg ivabradine HC1, preferably 2.5 to 10 mg ivabradine, particularly 5 or 7.5 mg ivabradine,

1 to 350 mg organic solvent, preferably 1.5 to 50 mg organic solvent, particularly 4.5 to 35 mg organic solvent,

1 to 400 mg carrier, preferably 1.5 to 60 mg carrier, particularly 5 to 45 mg carrier. The composition of the present invention can be applied in form of an oral dosage form, in particular in form of a solid oral dosage form. Thus, another object of the present invention is a solid oral dosage form comprising an ivabradine hydrochloride composition according to the present invention and further pharmaceutical excipient(s).

The pharmaceutical excipients are excipients with which the person skilled in the art is familiar, such as those which are described in the European Pharmacopoeia (Ph. Eur.) and/or in the US Pharmacopoeia (USP). In a preferred embodiment of the present invention the oral dosage form can further comprise one or more excipients(s) selected from surfactants (d), fillers (e), binders (f), disintegrants (g), lubricants (h) and glidants (j).

Surfactants (d) 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. Common surfactants are alkylsulfates (for example sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates and the like. Surfactants can be used in an amount of 0 to 2% by weight, preferably of 0.1 to 1.5% by weight, based on the total weight of the oral dosage form.

It is particularly preferred that the oral dosage form of the present invention does not contain a surfactant. Fillers (e) or diluents can be used to increase the bulk volume and weight of a low- dose drug to a limit at which a pharmaceutical dosage form can be formed. Fillers should fulfil several requirements, such as being chemically inert, non- hygroscopic, biocompatible, easily processable and possessing good biopharmaceutical properties. Examples of fillers are lactose, sucrose, glucose, mannitol, calcium carbonate, cellulose and others. Fillers (e) can be used in an amount of 0 to 25% by weight, preferably 1 to 20% by weight, based on the total weight of the dosage form. Binders (f) may be added to the pharmaceutical formulation in order to ensure that oral dosage forms, preferably tablets, can be formed with the required mechanical strength. The binder can, for example, be starch, polyvinyl pyrrolidone or cellulose derivatives. The binding agent can be present in an amount of 0 to 20% by weight, preferably 1 to 18% by weight, more preferably 2 to 15% by weight, in particular 3 to 12% by weight, based on the total weight of the pharmaceutical formulation.

Disintegrants (g) are compounds which enhance the ability of the dosage form, preferably the ability of the tablet to break into smaller fragments when in contact with a liquid, preferably water. Preferred disintegrants are sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone (crospovidone), sodium carboxymethyl glycolate (for example Explotab^®), swelling polysaccharide, for example soy polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof or protein, for example formaldehyde-casein, sodium bicarbonate or mixtures thereof. More preferred are sodium carboxymethyl cellulose and cross-linked polyvinyl pyrrolidone (crospovidone). Disintegrants can be used in an amount of 0 to 15% by weight, preferably of 1 to 12% by weight, more preferably 3 to 10% by weight, based on the total weight of the dosage form.

The function of lubricants (h) is reported to ensure that tablet formation and ejection can occur with low friction between the solid and the die wall. Further, lubricants can generally increase the powder flowability. The lubricant is preferably a stearate or fatty acid, more preferably an earth alkali metal stearate, such as magnesium stearate. The lubricant is suitably present in an amount of 0 to 2% by weight, preferably of about 0.1 to 1.0% by weight, based on the total weight of the dosage form.

Glidants j) can also be used to improve the flowability. Traditionally, talc was used as glidant, but is nowadays nearly fully replaced by colloidal silica (for example Aerosil^®). Preferably, the glidant can be present in an amount of 0 to 3% by weight, more preferably 0.1 to 2.5% by weight, in particular 0.25 to 2.0% by weight based on the total weight of the dosage form.

It lies in the nature of pharmaceutical excipients that they sometimes can perform more than one function in a pharmaceutical formulation. In this regard it is generally noted that due to the nature of pharmaceutical excipients it cannot be excluded that a certain compound meets the requirements of more than one of components (b) or (c) and (d) to (j). Therefore, colloidal silica (Aerosil) may function as a carrier for forming the composition according to the invention as well as a pharmaceutical excipient (j), i.e. the fact that colloidal silica is used as a component for forming the composition according to the invention does not mean that it cannot also be acting as a glidant (j).

However, in order to enable an unambiguous distinction, it is preferred in the present application that one and the same pharmaceutical compound can only function as one of the compounds (b) or (c) and (d) to (j). For example, if microcrystalline cellulose functions as a carrier (c), it cannot additionally function as a disintegrant (g), even though microcrystalline cellulose also exhibits a certain disintegrating effect.

The oral dosage form of the present invention can preferably comprise the following amounts of components:

1 to 400 mg carrier, preferably 1.5 to 60 mg carrier, particularly 5 to 45 mg carrier 0 to 20 mg surfactant, preferably 2 to 15 mg surfactant, particularly 4 to 10 mg surfactant,

0 to 250 mg filler, preferably 25 to 200 mg filler, particularly 40 to 100 mg filler, 0 to 125 mg binder, preferably 15 to 100 mg binder, particularly 25 to 75 mg binder,

0 to 100 mg disintegrant, preferably 5 to 75 mg disintegrant, particularly 10 to 50 mg disintegrant,

0 to 25 mg glidant, preferably 1 to 15 mg glidant, particularly 2 to 7 mg glidant, 0 to 15 mg lubricant, preferably 1 to 10 mg lubricant, particularly 2 to 8 mg lubricant. Alternatively, the oral dosage form of the present invention can preferably comprise the following amounts of components:

0 to 25 mg glidant, preferably 1 to 15 mg glidant, particularly 2 to 7 mg glidant,

0 to 15 mg lubricant, preferably 1 to 10 mg lubricant, particularly 2 to 8 mg lubricant. In a preferred embodiment the dosage form comprises

1 to 25 wt.% ivabradine,

5 to 50 wt.% organic solvent,

5 to 40 wt.% carrier,

0 to 2 wt.% surfactant

0 to 25 wt.% filler,

0 to 20 wt.% binder,

0 to 15 wt.% disintegrant,

0 to 2 wt.% lubricant and

0 to 3 wt.% glidant,

based on the total weight of the oral dosage form.

In an alternatively preferred embodiment the dosage form comprises

1 to 15 wt.% ivabradine,

5 to 20 wt.% organic solvent,

5 to 20 wt.% carrier,

0 to 2 wt.%) surfactant

0 to 75 wt.% filler,

0 to 20 wt.% binder,

0 to 15 wt.% disintegrant, 0 to 2 wt.% lubricant and

0 to 3 wt.% glidant,

based on the total weight of the oral dosage form. In a still further embodiment of the present invention the oral dosage form can be a capsule or a tablet, more preferably a tablet, for peroral use. Alternatively, the solid oral dosage form can be filled as powder or granulate into devices like sachets or stick-packs. The present invention further relates to a method for producing a composition according to the invention. Hence, a further subject of the present invention is a method for producing a composition comprising dissolved ivabradine (a), organic solvent (b) and carrier (c) comprising the steps of i) dissolving ivabradine in organic solvent (b),

ii) mixing carrier (c) and solution of step i) and

iii) optionally milling and/or sieving the mixture of step ii)

Generally, the comments made above for ivabradine, organic solvent and carrier can also apply to the method of the present invention.

In step i) of the method of the invention ivabradine is dissolved in organic solvent (b). The term "dissolving" means that a substance, such as ivabradine, is brought into contact with the solvent, preferably with a solvent or solvent mixture as defined above for compound (b), e.g. a mixture of polyethylene glycols having an average molar weight of 190 to 210 g/mol (PEG 200) or 1 ,2-propyleneglycol, wherein the solvent wets the surface of the substance or the substance can be completely dissolved in the solvent. When a clear solution is obtained and no ivabradine (crystals) can be detected by visual control, this can be regarded as a complete dissolving of ivabradine in an organic solvent.

In a preferred embodiment ivabradine is preferably added to organic solvent. It is further preferred that the organic solvent is preferably stirred and/or heated, preferably to a temperature of about 80°C.

In a preferred embodiment ivabradine can be dissolved in organic solvent (b), preferably under stirring during the dissolving step, preferably at a stirring speed of 300 to 450 rpm (rotations per minute). Additionally, it is preferred that the solvent is at an elevated temperature, preferably at about 80°C, during the dissolving step. Further, ivabradine is preferably added in crystalline form. Further, to support the formation of the solution of step i) ivabradine in organic solvent can be subjected to a mechanical treatment, such as ultrasonic treatment. Generally, ultrasonic treatment can be carried out by immersing ivabradine and organic solvent into an ultrasonic device, for example an ultrasonic bath. Examples of ultrasonic treatment are hydrodynamic cavitation, sono-fragmentation and/or sono-cavitation or co-grinding. For example, ultrasonic treatment can be carried out with Tesla ultrasonic equipment.

Ultrasonic treatment can preferably be performed by using ultrasonic waves having a frequency of 5 to 100 kHz, more preferably of 10 to 80 kHz. Furthermore, ultrasonic treatment is preferably performed by using ultrasonic waves having an intensity of 50 to 5000 W, more preferably 500 to 1000 W. As an example, 1000 W and 20 kHz or 500 W and 58 kHz can be used.

Usually, the mechanical treatment can be carried out for 1 to 30 minutes, preferably for 5 to 20 minutes.

Once the ivabradine is completely dissolved in organic solvent (b) in step ii), carrier (c) and the solution of step i) can be mixed.

In a preferred embodiment carrier (c) is added to the solution of step i). It is preferred that the solution of step i) is at elevated temperature, preferably about 80°C, when the mixing with carrier (c) is carried out. Further, the solution is preferably stirred, preferably at a stirring speed of 300 to 550 rpm during the mixing step ii). In a preferred embodiment the mixture of step ii), preferably after being allowed to cool to 23 °C, can be obtained as a powder-like material.

In an alternative embodiment further pharmaceutical active agent can be added to the mixture between step ii) and optional step iii).

In optional step iii) the mixture of step ii) can preferably be milled and/or sieved. The milling can preferably 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 a rotor mill. A planetary ball mill is preferably used.

The milling time is preferably 0.5 minutes to 30 minutes, preferably 1 to 15 minutes, more preferably 3 to 7 minutes.

It is preferred that the sieving of the mixture of step iii) can be carried out with a sieve having a mesh size of 25 to 1000 μπι, preferably 50 to 800 μηι, especially 100 to 600 μπι.

Further, the subject of the present invention relates to a method for preparing the oral dosage form of the invention comprising the steps: i) dissolving ivabradine in organic solvent (b),

ii) mixing carrier (c) and the solution of step i),

iii) optionally milling and/or sieving the mixture of step ii),

iv) optionally adding further excipient(s) to the mixture of step ii) or step iii),

v) optionally granulating the mixture of step ii), step iii) or step iv) vi) processing the mixture of step ii), step iii), step iv) or the granulates of step v) into an oral dosage form.

In steps i) to iii) a composition according to the present invention is provided, i.e. all the above process steps i), ii) and iii) leading to the present composition also apply to the process for preparing the present oral dosage form.

In step iv) additional further excipient(s) and/or further pharmaceutically active agent can optionally be added to the mixture of step ii) or step iii). During or after the addition of the optional excipients and/or further pharmaceutically active agent the resulting mixture can preferably be blended. The excipients can preferably be selected from the excipients (d), (e), (f), (g), (h) and j) as described above.

In step v) the mixture of step ii), step iii) or step iv) 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 of the invention, granulating the mixture from step iv) can be performed, for example, by "slugging", using a large heavy- duty rotary press and breaking up the slugs into 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 vi) the mixture of step ii), step iii), step iv) or the granulates of step v) is processed into a solid oral dosage form. Processing the mixture of step ii), step iii), step iv) or step v) into a solid oral dosage form can preferably comprise filling said mixture into capsules, preferably hard gelatine capsules. Optionally, processing the mixture of step ii), step iii) or step iv) into tablets can be carried out by compressing said formulation on a rotary press, e.g. on a Fette^® (Fette GmbH, Germany) or a Riva piccola (Riva, Argentina). The main compression force can range from 1 to 50 kN, preferably 3 to 40 kN. The resulting tablets can have a hardness of 30 to 400 N, more preferred of 50 to 250 N, particularly preferably of 30 to 180 N, more preferably 40 to 150 N, wherein the hardness can be measured according to Ph.Eur. 6.0, Chapter 2.9.8. For the optional filling of the formulation into capsules, dependent dosing systems (for example an auger) or preferably independent dosing systems (for example MG2, Matic (IMA)) can be used.

Further, the dosage form, preferably the tablet, of the invention preferably has a content uniformity, i.e. a content of active agent(s) which lies within the concentration of 90 to 110%, preferably 95 to 105%, especially preferred from 98 to 102% of the average content of the active agents(s). The "content uniformity" is determined with a test in accordance with Ph. Eur., 6.0, Chapter 2.9.6. According to that test, the content of the active agents of each individual tablet out of 20 tablets must lie between 90 and 1 10%, preferably between 95 and 105%, especially between 98 and 102% of the average content of the active agent(s). Therefore, the content of the active drugs in each tablet of the invention differs from the average content of the active agent by at most 10%, preferably at most 5% and especially at most 2%.

In addition, the resulting tablet preferably has a friability of less than 5%, particularly preferably less than 2%, especially less than 1%. The friability is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.7. The friability of tablets generally refers to tablets without coating. The pharmaceutical formulation of the invention may be a peroral tablet which can be swallowed unchewed. The tablet can preferably be film coated.

Generally, film coatings that do not affect the release of the active agent(s) and film coatings affecting the release of the active agent(s) can be employed with tablets according to invention. The film coatings that do not affect the release of the active agent(s) are preferred.

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), polyvinylpyrrolidone (PVP) and mixtures thereof. These polymers can have a weight-average molecular weight of 10,000 to 150,000 g/mol. In an alternative preferred embodiment, the film coating can affect the release of the active agent. Examples for film coatings affecting the release of the active agent are gastric juice-resistant film coatings and retard coatings.

In a preferred embodiment the film can have a thickness of 2 μηι to 150 μηι, preferably from 10 to 100 μιη, more preferably from 20 to 60 μηι.

In a preferred embodiment the dosage form of the invention is for modified release. In that case the release profile of the pharmaceutical formulation, preferably of the tablet, according to USP method (USP paddle apparatus, 900 ml test medium, in phosphate buffer at pH 6.8 and 37°C, 100 rpm) after 2 hours indicates a content release of 0 to 90%, preferably of 10 to 80%, further preferably 15 to 75%, more preferably 20 to 50% and particularly of 25 to 40 %.

In an alternatively preferred embodiment of the invention the dosage form is for immediate release. In that case the release profile of the pharmaceutical formulation, preferably of the tablet, according to USP method (USP paddle apparatus, 900 ml test medium, in phosphate buffer at pH 6.8 and 37°C, 100 rpm) after 15 minutes indicates a content release of at least 50%, preferably at least 70%, especially at least 90%. Further, the invention relates to a method for treating cardiac diseases, preferably angina pectoris, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising (a) dissolved ivabradine, (b) organic solvent with a boiling point of about 110°C to 350°C, and (c) solid carrier. For the pharmaceutical composition administered in the before-mentioned method the same applies as to the composition as described above in the text.

Further, the invention relates to the use of a saturated ivabradine solution for producing a solid oral dosage form, wherein said dosage form is free of crystalline ivabradine.

A saturated ivabradine solution is a solution containing so much ivabradine without forming a precipitate that the maximum of dissolved ivabradine is reached. The saturation of a solution may depend on its temperature.

Experimental Part

Analytical methods:

The compositions according to the invention were examined by X-ray powder diffraction and with solid state 1H MAS NMR.

X-ray powder diffraction

The measurements were performed as follows: The samples were measured on a D8 Advance powder X-ray diffractometer (Bruker-AXS, Karlsruhe, Germany) in a PMMA sample holder rotating at 20 rpm during the measurement (Bragg-Brentano geometry). Further conditions for the measurements are summarized below. The raw data were analysed with the program EVA (Bruker-AXS, Karlsruhe, Germany). radiation Cu K_al/ a.2

source 34kV/40mA

detector Vantec-1 (electronic window: 3° KB filter Ni (diffracted beam)

measuring circle diameter 435 mm

detector window slit 12 mm

anti-scatter slit 8 mm divergence slit v6.00 (variable)

soller slit (incident/diffracted beam) 2.5°

2Θ range 1° 2 < 2Θ < 55

step size /° 0.016°

step time 0.2 s

LC-MS

Instrument: Agilent 1200 coupled with Esquire HCT (Bruker Daltonics)

Column: Phenomenex CI 8; 2.6 μιη; 150 x 4.6 mm

Detection: UV/DAD (λ= 288.4 nm)

Column temp. : 40°C

Flow [mL/min] : 0.7

Injection volume: 3 xL

Solvent A: Acetonitrile

Solvent B: 0.2% formic acid and 0.1 % HFBA

Gradient: time [min] Solvent B [%]

0 70

10 50

12 30

15 15

17 15

17.5 70

23 70

MS parameters:

Dry temperature 340°C

Nebulizer: 45.0 psi

Dry gas: 5.0 1/min

Ion polarity: positive

Scan range: m/z 100 - 750

Solid state 1H MAS NMR

The analysis has been done to illustrate the typical features of NMR spectra of ivabradine hydrochloride at different physical states (crystalline, amorphous, viscous liquids and gels, and solutions). The experimental parameters were optimized to highlight differences between the samples and to allow identification (recognition) of different physical states.

For comparison, in this study a system of a crystalline model drug (Tm=137°C), an amorphous model drug prepared by quench cooling with Tg =33°C, and a 10% w/w solution of the model drug in deuterated ethanol was used.

Methods and experimental parameters

All NMR spectra were measured using Bruker AVANCE III HD solid state NMR spectrometer (Karlsruhe, Germany, 2013) at spinning frequency ω_Γ/2π = 10 kHz. ^lH MAS NMR spectra were recorded using the single-pulse experiment with a repletion delay 4s and a number of scans of 512.

Ultra Performance Liquid Chromatography UPLC

For the determination of the release of ivabradine, the following method was used. Details are summarized below.

Instrument: Agilent 1290

Injection volume: 2.5 μΐ_^

Flow: 0.7 mL/min

Column: Phenomenex Kinetex C₁₈ 150 x 4.6 mm; dp = 2.6 μηι

Oven temperature: 40 °C

Solvent A: water with 0.2% formic acid and 0.1 % heptafluorobutyric acid

Solvent B: acetonitrile

Gradient: Time [min] Solvent A [%] Solvent B [%]

0.0 70 30

9.0 50 50

9.1 70 30

10.0 70 30

Stop time: 10.0

Detection: UV/DAD (λ= 288.4 nm) EXAMPLES

Ivabradine hydrochloride was dissolved in solvent at 80°C under stirring. To the clear solution carrier was added portionwise (0.05 g) at 80°C until the mixture is a free flowing homogenoous powder. The product was allowed to cool down to room temperature. The employed amounts of the compositions are specified in Table A.

TablerExamples 1 - 28

Example 29

Substance of example 1 and croscarmellose sodium were blended for 20 minutes, Prosolv SMCC 90 was added through a 355 mm sieve and subsequently blended for 30 minutes. Then, sieved magnesium stearate was added and the mixture was blended for further 2 min. The final blend was compressed into biconvex tablets of 7 mm diameter each containing

substance of example 1 22.90 mg (corresponds to 5 mg free base)

Prosolv SMCC90 63.52 mg

croscramellose sodium 10 mg

Aerosil 200 2.58 mg

Magnesium stearate 1 mg Example 30

Substance of example 21 and croscarmellose sodium were blended for 20 minutes, Prosolv SMCC 90 was added through a 355 mm sieve and subsequently blended for 30 minutes. Then, sieved magnesium stearate was added and the mixture was blended for further 2 min. The final blend was compressed into biconvex tablets of 7 mm diameter each containing

substance of example 21 22.90 mg (corresponds to 5 mg free base)

Prosolv SMCC90 63.52 mg

croscarmellose sodium 10 mg

Aerosil 200 2.58 mg

magnesium stearate 1 mg

Comparative examples:

Reference Example 1 (in analogy to example 13 of WO 2013/150544 A2):

A mixture of 0.5 g ivabradine hydrochloride and 0.5 g HPMC was dissolved in 10 mL n-butanol at room temperature. The solution was stirred for 15 minutes at room temperature and the solvent was distilled off under vacuum at below 75°C. The resulting solid was subjected to drying at 70°C for 3 hours to obtain 0.9 g of solid, amorphous ivabradine hydrochloride dispersed on hydroxypropyl methylcellulose.

Reference Example 2 (in analogy to example 18 of WO 2013/150544):

A mixture of 0.5 g ivabradine hydrochloride and 0.5g PEG1500 was dissolved in 10 mL n-butanol at RT. The solution was stirred for 15 minutes at room temperature and the solvent was distilled off under vacuum at below 75°C. The resulting solid was subjected to drying at 70°C for 3 hours to obtain 0.85 g of crystalline ivabradine hydrochloride with PEG1500.

RESULTS Figure A- l shows an overview of X-ray powder diffractograms of all used carriers.

Figure A-2 shows the 1H MAS NMR spectra of model drug in four different states: crystalline, amorphous at 30°C, amorphous at 80°C and dissolved at 30°C. As demonstrated on Figure A-2a and A-2b the crystalline solid deeply bellow the melting point (T_m = 137°C)as well as amorphous system close to the glass transition temperature (J_g = 33°C) are reflected by broad, featureless Ή MAS NMR spectra with the linewidth of central signal larger than 2000 Hz. The observed broadening of the signals is caused by strong ¹H-¹H dipolar interactions. It is well known that an ester substituent of the model drug is the highly mobile molecular segment executing fast high-amplitude flips and rotation motions. Consequently it is clear that even the fast and extensive internal motion of the specific function units does not significantly increase the spectral resolution. Moreover, even approaching the glass transition temperature T_g = 33°C at which the global motions are released does not lead to the narrowing 1H MAS NMR signals (Figure A-2b). Considerable increase in spectral resolution is observed at much higher temperature, ca. T = 75-80°C, when the glassy solid sample converts to a highly viscous melt. At this state the correlation frequency of the global molecular motion of the model drug is higher than the 1H NMR resonance frequency (500 MHz) of the applied 1H NMR experiment (Figure A2-c). In this case the linewidth of the signals decreases below ca. 500-400 Hz. Complete narrowing of the signals is, however, reached after dissolving of the sample in low-molecular-weight solvent such as ethanol (Figure A-2d) when the halfwidth of the signals dramatically decrease to be ca. 1-2 Hz.

In summary, the 1H MAS NMR (7- 15 kHz) reveals the following: a) Broad and featureless signals with line-widths of ca. 20000-3000 Hz detected in 1H MAS NMR spectra measured at MAS frequency 7-15 kHz indicate rigid, completely immobilized crystalline and/or amorphous systems. These systems are below the melting temperature (T_m), critical temperature of pour point (T₀) and glass transition temperature (T_g).

b) Narrowed signals with the line- width between 3000 and 500 Hz then indicate systems with partially released segmental and molecular motions. Such behavior is typical for amorphous organic solids above glass transition temperature T_g and near the critical temperature of pour point ( T_c).

c) Relatively well-resolved 1H MAS spectra with the narrow signals of the line- width usually 500-300 Hz reflect a highly solvated amorphous phase, strongly swollen gels and/or highly viscous solutions. Medium viscous solutions are reflected by the signals with a line- width of ca. 300-10 Hz, while highly diluted solutions produce extremely narrowed signals with a line-width of 10- 1 Hz.

In Figure B-l the diffractogram of Example 1 is shown. Further, diffractogram according to Figure B-2 was recorded after 12 weeks storage at ambient conditions, respectively. The diffractograms essentially look like the diffractogram of pure Neusilin (compare with Figure A-l).

The organic solvent 1 ,2-propanediol has a boiling point of 187°C at atmospheric pressure and a vapour pressure constant of 0.1 mbar at 20°C. Although a highest possible concentration of ivabradine HC1 in solution was obtained, there is no indication that ivabradine HCl crystallises in the present sample, i.e. ivabradine hydrochloride stays dissolved.

In Figure B-3 the 1H MAS NM spectrum of example 1 is recorded. The solvent signals as well as the signals of ivabradine HCl are well resolved and can be easily identified. The line-widths of the solvent signals of ca. 40-60 Hz indicate that the solvent molecules are highly mobile. The observed broadening of the ivabradine HCl signals reflect a slightly restricted molecular dynamics which indicates a viscous solution.

In Figure C-l the diffractogram of Example 7 is shown. Further, diffractogram according to Figure C-2 was recorded after 12 weeks storage at ambient conditions, respectively. The diffractograms essentially look like the diffractogram of pure celite (compare with Figure A-l).

The organic solvent 1,2-propanediol has a boiling point of 187°C at atmospheric pressure and a vapour pressure constant of 0.1 mbar at 20°C. Although a highest possible concentration of ivabradine HCl in solution was obtained, there is no indication that ivabradine HCl crystallises in the present sample, i.e. ivabradine hydrochloride stays dissolved.

In Figure C-3 the 1H MAS NMR spectrum of example 7 is recorded. The spectrum is dominated by the set of narrow central signals that are accompanied by the considerably less intensive spinning-side bands (also narrow signals) The central signals (C-3-b) are well resolved with the line width ranging from 30 Hz (signal #a, solvent; signal #6 ivabradine HCl) to 80 Hz. The broader signal (ca. 200 Hz) was found for liable OH groups (solvent + ivabradine HCl). Because the narrow signals were detected for both components, the obtained data indicate that solvent molecules as well as molecules of the active compound are highly mobile executing global high-amplitude and high-frequency motions.

In Figure D-l the diffractogram of Example 10 is shown. Further, diffractogram according to Figure D-2 was recorded 12 weeks storage at ambient conditions, respectively. The diffractograms essentially look like the diffractogram of pure SBA-15 (compare with Figure A-l).

The organic solvent PEG 200 has a boiling point of more than 250°C at atmospheric pressure and a vapour pressure of less than 0.01 mm Hg at 20°C. Although a highest possible concentration of ivabradine HCl in solution was obtained, there is no indication that ivabradine HCl crystallises in the present sample, i.e. ivabradine hydrochloride stays dissolved.

In Figure D-3 the 1H MAS NMR spectrum of example 10 is recorded. The spectrum is dominated by the strong narrow central signals with the line-width of ca. 30-60 Hz. These strong signals that are accompanied by the considerably less intensive spinning-side bands can be attributed to the molecules of PEG 200 solvent. Close inspection of the spectrum further revealed a set of low-intensive signals that can be assigned to ivabradine HCl (Figure D-3-b). The line- width of the ivabradine HCl signals if relatively low oscillating between 40-70 Hz. Consequently we interpret that the solvent molecules as well as the molecules of the ivabradine HCl are mobile executing high-amplitude and high-frequency motions. In Figure E-l the diffractogram of Example 18 is shown. Further, diffractogram according to Figure E-2 was recorded after 12 weeks storage at ambient conditions, respectively. The diffractogram essentially look like the diffractogram of pure MCM-48 (compare with Figure A-l). The organic solvent 2,3-butanediol has a boiling point of 184°C at atmospheric pressure and a vapour pressure constant of 0.2 mbar at 20°C. Although a highest possible concentration of ivabradine HCl in solution was obtained, there is no indication that ivabradine HCl crystallises in the present sample, i.e. ivabradine hydrochloride stays dissolved.

In Figure E-3 the 1H MAS NMR spectrum of example 18 is recorded. The spectrum reveals that the 2,3-butanediol signals as well as the signals of ivabradine HCl are relatively well resolved and can be easily identified. The line-widths of the solvent signals of ca. 30-40 Hz indicated that the solvent molecules are highly mobile. Similarly the ivabradine HCl signals are relatively well resolved with the line-widths of the aromatics signals of ca. 40 Hz indicating the high mobility of the ivabradine HCl molecules.

In Figure F the recovery of active ingredient ivabradine HCl from various carriers was determined to assure that Ivabradine is releasable from the carrier and is available for resorption.

As a test medium, acidic medium was chosen, as it is present in the stomach. 91mg of ivabradine HCl on carrier was dissolved in 2 ml 0.01 M HCl, stirred with 250 rpm at 37°C and kept for 15, 30 and 60 min respectively. A 100 μΐ sample was withdrawn, centrifuged at 13000 rmp and diluted 1 :10 with 0.01M HCl. The amount of ivabradine, which was released from the carrier was analysed by UPLC. In Figures G and G-l the diffractogram and the 1H MAS NMR of Reference Example 1 are shown, respectively.

The diffractogram and the 1H MAS NMR of Reference Example 1 reveals that ivabradine hydrochloride in Reference Example 1 forms a rigid amorphous phase that is dispersed in rigid amorphous excipient HPMC. Thus, in Reference Example 1 ivabradine hydrochloride is present in a solid form. That fact gets particularly clear when figure G-l is compared with the solid model substance as shown in figure A- 2(a) or A2-(b). In Figure H the diffractogram of Reference Example 2 is shown. The spectrum reveals that ivabradine hydrochloride is in a crystalline state. Thus, in Reference Example 2 ivabradine hydrochloride is present in a solid form as well.

Claims

1. Pharmaceutical composition comprising

(a) dissolved ivabradine,

(b) organic solvent with a boiling point of 110° to 350° C and

(c) solid carrier.

2. Composition according to claim 1, wherein the organic solvent (b) has a boiling point of 170°C to 345°C.

3. Composition according to claim 1 or 2, wherein the organic solvent (b) has a density of 0.95 to 1.30 g/ml measured at 20°C.

4. Composition according to any one of claims 1 to 3, wherein the weight ratio of dissolved ivabradine (a) to organic solvent (b) is from 1 : 1 to 1 :20.

5. Composition according to any one of claims 1 to 4, wherein the carrier (c) is a brittle substance, having a yield pressure of 80 MPa to 500 MPa.

6. Composition according to any one of claims 1 to 5, wherein the carrier (c) is an organic polymer or an inorganic substance.

7. Composition according to any one of claims 1 to 6, wherein the carrier (c) possesses a specific surface area from 75 to 350 m²/g, whereby the specific surface area is measured according to Ph. Eur. 6.0, Chapter 2.9.26.

8. Composition according to any one of claims 1 to 7, wherein the carrier (c) is a silicate, preferably a magnesium aluminosilicate, or mesoporous silica.

9. Composition according to any one of claims 1 to 8, wherein the weight ratio of dissolved ivabradine (a) to carrier (c) is from 1 :1 to 1 : 10.

10. Oral dosage form comprising a composition according to any one of claims 1 to 9 and optionally further pharmaceutical excipient(s).

1 1. Oral dosage form according to claim 10, wherein the dosage form comprises

1 to 15 wt.% ivabradine,

5 to 20 wt.% organic solvent, 5 to 20 wt.% carrier,

0 to 2 wt.% surfactant

0 to 75 wt.% filler,

0 to 20 wt.% binder,

0 to 15 wt.% disintegrant,

0 to 2 wt.% lubricant and

0 to 3 wt.% glidant,

based on the total weight of the oral dosage form.

12. Method for producing a composition according to any one of claims 1 to 9 comprising the steps of

i) dissolving ivabradine (a) in organic solvent with a boiling point of 110° to 350°C (b)

ii) mixing carrier (c) and solution of step i)

iii) optionally milling and/or sieving the mixture of step ii).

13. Method for producing an oral dosage form according to claim 10 or 11 comprising the steps of

i) dissolving ivabradine (a) in organic solvent with a boiling point of 1 10° to 350°C (b)

ii) mixing carrier (c) and solution of step i)

iii) optionally milling and/or sieving the mixture of step ii)

iv) optionally adding further excipient(s) to the mixture of step ii) or step iii)

iii) processing the mixture of step ii), step iii) or step iv) into an oral dosage form.

14. A method for treating cardiac diseases, preferably angina pectoris, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 9 or a dosage form according to claims 10 or 11.