WO2015021949A1

WO2015021949A1 - A thermodynamically stable solid solution of agomelatine for use in a pharmaceutical formulation

Info

Publication number: WO2015021949A1
Application number: PCT/CZ2014/000088
Authority: WO
Inventors: Jaroslav Rezac; Anna Hanovska; Daniel Pribyl; Ondrej Dammer; AIena PROKOPOVA
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2013-08-13
Filing date: 2014-08-13
Publication date: 2015-02-19
Anticipated expiration: 2016-02-13
Also published as: CZ2013621A3

Abstract

The invention provides a thermodynamically stable solid solution of agomelatine, containing agomelatine dissolved in a polymeric carrier, which is a copolymer of polyvinylpyrrolidone with polyvinyl acetate in the weight ratio of 3:2 (Kollidon VA64), its processes for preparing the same and pharmaceutical ' compositions containing agomelatine (N-[2-(7-methoxy-1-naphtyl)ethyl]-acetamide) of formula (I) and a process for the manufacture thereof.

Description

A THERMODYNAMICALLY STABLE SOLID SOLUTION OF AGOMELATINE FOR USE IN A PHARMACEUTICAL FORMULATION

Technical Field The invention relates to pharmaceutical compositions containing a solid solution of agomelatine (N-[2-(7-methoxy-1-naphtyl)ethyl]acetamide) of formula (I),

and a method for the preparation thereof.

Background Art

Formulations containing agomelatine belong to the group of antidepressants. Agomelatine is a melatonergic agonist (of the ΜΊι and MT₂ receptors) and an antagonist of the 5-HT₂c serotonergic receptors.

Agomelatine was first introduced in the patent EP 0 447 285 (Adir et Compagnie). There are a number of polymorphic forms of agomelatine. For example, the application WO2005077887 (Servier) describes Form II of agomelatine, the application WO2007015003 (Servier) describes Form III of agomelatine, the application O2007015002 (Servier) describes Form IV of agomelatine, the application WO2007015004 (Servier) describes Form V of agomelatine, the application WO2009095555 (Servier) describes Form VI of agomelatine and the application WO2011006387 (Zhejiang Huahai Pharmaceutical Co., Ltd.) describes Forms A, B and C of agomelatine.

Out of these polymorphic forms, Form II is the most stable one. During the production and storage of preparations containing agomelatine of a polymorphic other than Form II, generally the other form or forms undergo transformation to the thermodynamically more stable Form II sooner or later.

Agomelatine is marketed in two products (Valdoxan and Thymanax, both of the 25 mg strength) of the company Sender, In these products agomelatine is present in the polymorphic Form Π.

Pharmacokinetic studies have shown that the bioavailability of agomelatine is very low when administered orally as compared to parenteral administration and that it is strongly variable when administered to different patients (inter-individual variability) and even when agomelatine is repeatedly administered to the same patient (intra- individual variability). Problems with bioavailability and variability of pharmaceutical compositions of agomelatine with instant release have incited looking for such formulations that would overcome these problems.

It is known from literature that solubility, and thus dissolution, consequently bioavailability of substances that are poorly soluble in water can be increased by their transformation to a solid solution.

The document of the company BASF Hot Melt Extrusion with BASF Pharma Polymers Extrusion Compendium, August, 2010, describes preparation of solid solutions of poorly soluble substances (i.a., agomelatine) by melting with polymers, preferably with Kollidon VA- 64, Soluplus and Kollidon 30. A melting temperature in the range of 90 - 140°C is recommended; after solidification of the melt the extrudate is ground and the solid ground solution is used for preparation of pharmaceutical compositions.

However, when preparing solid solutions according to the above recommendations, the authors of the present invention did not manage to prepare a genuine solid solution without detectable agomelatine particles. Instead, a solid dispersion was formed, either right after the production or later during stability testing by recrystallization of agomelatine.

The authors of the invention have finally succeeded in finding the parameters that influence the resulting state of the material - whether it will have the form of a solid solution or solid dispersion not only immediately after the production, but also after processing into a pharmaceutical formulation throughout the stability testing period. The present invention provides biologically available pharmaceutical compositions containing a thermo dynamically stable solid solution of agomelatine that ensure uniform releasing of agomelatine, guarantee a suitable dissolution profile and do not exhibit undesired recrystallization of agomelatine.

Disclosure of Invention

The invention provides a thermodynamically stable solid solution of agomelatine for use in a pharmaceutical formulation with the concentration of agomelatine in a polymeric carrier of up to 45% by weight, related to the weight of the solid solution, the particle size distribution of which after grinding is such that at most 60% by weight of particles are smaller than 0.1 mm. The polymeric carrier used is a copolymer of polyvinylpyrrolidone with polyvinyl acetate (copovidone) in the weight ratio of 3:2 (Kollidon VA64). Also claimed is a pharmaceutical composition containing this stable solid solution of agomelatine and non-hygroscopic pharmaceutically acceptable auxiliary substances with a low content of water. These solid solutions as well as pharmaceutical compositions are thermodynamically stable, which has been confirmed by stability testing at various conditions (of natural and accelerated stability) and are suitable in terms of dissolution profiles.

Detailed description of the invention The invention provides thermodynamically stable solid solutions of agomelatine for use in a pharmaceutical formulation with the concentration of agomelatine in a polymeric carrier of up to 45%» by weight, related to the weight of the solid solution, the particle size distribution of which after grinding is such that at most 60% by weight of particles are smaller than 0.1 mm, the polymeric carrier used being a copolymer of polyvinylpyrroUdone with polyvinyl acetate (copovidone) in the weight ratio of 3:2 (Kollidon VA64). Other objects of this invention are pharmaceutical formulations containing said solid solution, which have the advantage in a faster and better solubility than that of a reference agomelatine formulation containing agomelatine particles (see Figure 10).

The solid solution of agomelatine and such a polymeric carrier is thermodynamically stable and does not exhibit undesired recrystallization of agomelatine. Compositions containing the solid solution of agomelatine and the polymeric carrier in accordance with the present invention dissolve more quickly and better than the reference agomelatine preparation.

For the preparation of the solid solution of agomelatine all information contained in the BASF document Hot Melt Extrusion with BASF Pharma Polymers Extrusion Compendium, August, 2010, which describes preparation of solid solutions of poorly soluble substances (i.a., agomelatine) by melting with polymers, preferably with Kollidon VA-64, Soluplus and Kollidon 30, was first used. A melting temperature in the range of 90 - 140°C is recommended; after solidification of the melt the extrudate is ground and the solid ground solution is used for preparation of pharmaceutical compositions.

Nevertheless, instead of obtaining a solid amorphous solution undesired recrystallization of agomelatine occurred in some cases, i.e., instead of a solid solution a solid dispersion of agomelatine particles was formed. However, the use of such solid dispersions in a formulation led to very poor dissolution profiles (see Fig. 10) and it was necessary to find such parameters that would reliably guarantee that the resulting material will have the form of a solid solution (not a solid dispersion). As discussed below, the authors of the invention have finally succeeded in finding such combination of parameters.

However, another surprise was that even in cases when the material was evaluated as a solid solution immediately after the production, recrystallization to a dispersion occurred later during the stability testing.

So it was necessary to continue looking for suitable conditions given by a combination of optimal parameters under which no recrystallization would occur during the melt solidification process, during the storage of the solid solution or during preparation and storage of the pharmaceutical composition. Parameters that are essential for achieving the technical effect of the invention include the type of the polymeric carrier, the concentration of agomelatine in said polymeric carrier and the particle size of the ground solid solution. On the other hand, those parameters that have proved to be irrelevant for achievement of the technical effect of the invention include, e.g., the process temperature (virtually any melting temperature can be used in the range where reliable melting of the active substance and the polymer occurs and where the active substance is not subject to degradation at the same time), cooling rate, type of equipment for the preparation of the solid solution, grinding method of the solid solution (three device types were tested) etc.

A "solid solution" means a chemically and physically homogeneous amorphous material in which the molecules of the dissolved substance are homogeneously dispersed among the molecules of the carrier substance (the substance forrning the matrix of the solid solution) and in which no particles of the dissolved substance are detectable by any method known from the state of the art (e.g. an optical and electron microscope, FTIR microscopy, X-ray analysis, NMR).

A "solid dispersion" means a chemically and physically non-homogeneous material in which particles of the dissolved substance are detectable by a method known from the state of the art (e.g. an optical and electron microscope, FTIR microscopy, X-ray analysis, NMR).

Concentration of agomelatine in the solid solution

The concentration of agomelatine in the solid solution in accordance with the invention, which consists of agomelatine dissolved in a polymeric carrier, can be up to 45% by weight, conveniently 15 to 30% by weight, related to the weight of the solid solution.

In a preferred embodiment the concentration of agomelatine in the solid solution is 15% by weight, related to the weight of the solid solution. In another preferred embodiment the concentration of agomelatine in the solid solution is 30% by weight, related to the weight of the solid solution.

The ratio of agomelatine to the polymeric carrier in the solid solution in accordance with the invention is lower than 1 : 1.2 (by weight), conveniently from 1 : 1.2 to 1 : 5.7 (by weight).

Polymeric carrier The polymeric carriers mentioned in the BASF document as the preferred ones were tested, i.e. Kollidon VA-64 (copolymer of polyvinylpyrrolidone with polyvinyl acetate (copovidone) in the weight ratio of 3:2), Soluplus (copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol) and Kollidon 30 (polyvinylpyrrolidone with the molecular weight characterized by the K 30 value). The use of Kollidon 30 (polyvinylpyrrolidone with the molecular weight characterized by the K 30 value) has proved to be possible, but inconvenient. The glass transition temperature (Tg) of Kollidon 30 is 149°C and its working temperature is even 20 °C higher, while the melting temperature of agomelatine varies around 100°C. An optimal condition for the preparation of solid solutions is that the active substance and the polymeric carrier have similar melting temperatures, which is not fulfilled here, but in spite of this a solid solution of agomelatine could be prepared. However, the higher melting temperature of Kollidon 30 means higher energy costs and therefore no more stability or dissolution tests were carried out.

Soluplus has turned out to be absolutely unsuitable for preparation of a solid solution of agomelatine. When the copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol (Soluplus) was used, crystalline Form II of agomelatine was always at least partly detected in the extrudate, and in the final dosage form (coated tablets) crystalline Form II was detected immediately after the production (see comparative Example 3). With this polymer we did not manage to find conditions under which it would be possible to prepare a stable solid solution without admixed recrystallized dispersed particles of agomelatine.

A preferred polymeric carrier of this technical solution is the copolymer of polyvinylpyrrolidone with polyvinyl acetate (Kollidon VA64). When the other discussed parameters were met, the use of Kollidon VA64 resulted in production of stable forms of both the extrudate with a rougher particle size and the extrudate after grinding to a fine particle size, as well as to the final dosage form after production and during storage of packed tablets for 1 month at 40°C and the relative humidity of 75%. In terms of XRPD analysis, this is confirmation of absence of any crystalline form in the sample.

Particle size of the solid solution What was very surprising was the observation that the size of particles to which the solid solution is ground for use in pharmaceutical formulations had a great impact on stability of the solid solution. If the solid solution was ground too finely, immediately during the grinding or even gradually during the stability testing gradual recrystallization to an undesired solid dispersion occurred, which however exhibited very poor dissolution profiles when used in pharmaceutical formulations. It has been found out that to ensure stability of the solid solution and to prevent recrystallization of agomelatine from the solid solution to a solid dispersion it is necessary that, after grinding, at most 60% by weight of solid particles of the solid solution is smaller than 0.1 mm. From the point of view of using the solid solution in a pharmaceutical composition and of ensuring suitable dissolution profiles it is convenient if at least 20% by weight of particles of the ground extrudate are smaller than up to 100 micrometers, at least 70% by weight of particles of the ground extrudate are smaller than 500 micrometers and at least 90% by weight of particles of the ground extrudate are smaller than 1000 micrometers.

Pharmaceutical formulations containing a solid solution of agomelatine.

Another aspect of the present invention provides pharmaceutical compositions containing a solid solution of agomelatine and pharmaceutically acceptable auxiliary substances, e.g., fillers, disintegrants, binders and/or lubricants. Preferred auxiliary substances are those that have a low content of free water (up to 7% by weight) and are non-hygroscopic.

Microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, lactose monohydrate, mannitol and/or sorbitol can be used as fillers. Microcrystalline cellulose is preferred, especially microcrystalline cellulose with a water content of max. 1.5% by weight (e.g. type Avicel ΡΗΠ2).

Crosspovidone, low substituted hydroxypropyl cellulose and/or colloidal silicon dioxide can be used as disintegrants. Crosspovidone and silicon dioxide are convenient and a combination of these two disintegrants is especially preferred. Povidone, copovidone, hydroxypropyl cellulose and/or hydroxyethyl cellulose can be used as binders.

Magnesium stearate, calcium stearate, stearic acid and/or sodium stearyl fumarate can be used as lubricants. A preferred solution includes the use of a combination of magnesium stearate and stearic acid. Pharmaceutical formulations can be prepared in any commonly used form for oral administration, e.g., in the form of capsules, tablets or coated tablets, and can be packed in, e.g., vials or blister packs of a foil containing a PVC layer, PE layer and PVDC layer sealed with an aluminum foil (called PVC/PE/PVDC//ALU blisters) or in blister packs of an aluminum foil closed with an aluminum foil (called ALU// ALU blisters), in a normal or inert atmosphere. The normal atmosphere means air and an inert atmosphere means a gas with oxygen content lower than 21% by vol. An inert atmosphere conveniently consists of at least 95% by volume of nitrogen or 95% by volume of argon.

Preparation of solid solutions

The solid solutions of agomelatine and a polymeric carrier in accordance with the invention can be prepared using the hot melt extrusion (HME) technology.

It consists in heating of a pre-homogenized mixture of agomelatine and the polymeric carrier, and optionally other auxiliary substances, to a suitable temperature at which agomelatine can be dissolved in the melted polymeric carrier. In a preferred embodiment agomelatine of the crystalline Form I is used. The process temperature must not be too high to avoid chemical decomposition of the active substance, but sufficiently high to produce a clear solution of the active substance in the polymeric carrier.

For the preferred copolymer of polyvinylpyrrolidone with polyvinyl acetate in the weight ratio of 3:2 (Kollidon VA64) an optimum temperature of 120°C to 140°C was verified. This has been confirmed by and XPRD analysis, which proved absence of the crystalline form. At lower temperatures, e.g., 95°C, or 110°C, a solid dispersion, not a solid solution, of agomelatine was produced. Using the melting temperature of 120°C is especially convenient for economic reasons. During the extrusion process after the dissolution of agomelatine in the polymer the obtained mixture is gradually extruded through a matrix of suitable dimensions, e.g., 3 - 6 mm, and then cooled by air. After cooling and solidification the obtained extrudate is ground with a rotating knife or other technique into small pieces and is ready for further processing. The production of extrudate has been verified in two types of extruders (Thermofisher, ThreeTec). The hourly quantity of produced extrudate has been tested to be up to 1 kg h and the extruder torque was 35-125 N.m.

The resulting solid solution can be further used for the production of a pharmaceutical composition.

Preparation of pharmaceutical formulations

With respect to the properties of the active substance, technologies excluding any solvent (e.g. water or ethanol) were used for the preparation of a pharmaceutical composition containing a solid solution of agomelatine. These include direct tabletting method or dry granulation method.

Direct tabletting represents a technological process wherein auxiliary substances are gradually, in multiple steps, sieved and mixed with the extrudate containing agomelatine in such a way that a sufficiently homogeneous mixture of substances for tableting results. The cores are coated with a suspension consisting of common excipients. The direct tabletting process is convenient for its simplicity.

Dry granulation, e.g. compaction, may be an alternative method. Compaction means a production method wherein the extrudate containing agomelatine and other excipients are homogenized in one or more production steps, followed by compressing a band of compact material by the effect of pressure in a compactor, which band is subsequently ground in a sieving device to a defined particle size depending on the mesh size. The resulting granulate is either used directly to produce tablets, or one or more excipients are admixed and then it is used for the production of cores or tablets. The cores are coated with a suspension consisting of common excipients. The next production steps include tabletting and then coating and adjusting of tablets.

A more detailed description of the procedure in accordance with the invention is suggested in the examples. Brief Description of Drawings

Fig. 1: XPRD analysis— confirmation of absence of the crystalline form of agomelatine in the extrudate of Example 1 (1 - roughly ground extrudate, 2 - finely ground, 3 - pure polymer Kollidon VA64, 4 - comparative: agomelatme of crystalline Form I) Fig. 2: XPRD analysis - confirmation of absence of the crystalline form of agomelatine in cores made from the extrudate of Example 1 (1 - finely ground extrudate, 2 - cores made from this extrudate, 3 - verification of presence of magnesium stearate in the cores)

Fig. 3: XPRD analysis - confirmation of absence of the crystalline form of agomelatine in the extrudate from of 2 (1 - roughly ground extrudate, 2 - finely ground, 3 - comparative: agomelatine of crystalline Form II)

Fig. 4: XPRD analysis - confirmation of absence of the crystalline form of agomelatine in cores made from the extrudate of Example 2 (1 - finely ground extrudate, 2 - cores made from this extrudate, 3 - verification of presence of magnesium stearate, 4 - verification of presence of stearic acid in the cores) Fig. 5: XPRD analysis - confirmation of absence of the crystalline form of agomelatine in the extrudate of Example 3 (1 -finely ground extrudate, 2 - pure polymer Kollidon VA64, 3 - comparative: agomelatine of crystalline Form I)

Fig. 6: XPRD analysis - confirmation of absence of the crystalline form of agomelatine in the extrudate of Example 4 (1 -finely ground extrudate, 2 - pure polymer Kollidon VA64, 3 - comparative: agomelatine of crystalline Form I)

Fig. 7: XPRD analysis - confirmation of absence of the crystalline form of agomelatine in the extrudate of Example 5 (1 - finely ground extrudate, 2 - comparative: agomelatine of crystalline Form II)

Fig. 8: XPRD analysis - confirmation of absence of the crystalline form of agomelatine in the extrudate of Example 6 (1 - finely ground extrudate, 2 - comparative: agomelatine of crystalline Form II)

Fig. 9 : XPRD analysis - confirmation of presence of a mixture of crystalline Form II in the finely ground extrudate in Example 7 (1 - roughly ground extrudate, 2 - finely ground extrudate, 3 - comparative: agomelatine of crystalline Form II) Fig. 10: Dissolution profiles

1 - Example 1 (batch 230611), 2 - Example 2 (batch 200511), 3 - Example 7 (batch 210511), 4 - reference product

(batch 200511 - Example 2 and batch 230611 - Example 1 to an even higher extent represent solid solutions exhibiting faster dissolution profiles than the reference product; on the other hand, batch 210511 - Example 7 - represents a solid dispersion and shows a considerable deceleration of the dissolution profile as compared to the reference product)

Examples

* ratio of agomelatine to the polymeric carrier

** % of weight of extrudate particles smaller than 0.1 mm EXAMPLE 1

Agomelatine and Kollidon VA64 in the weight ratio of 15 : 85 are sieved through a 1.0 mm sieve and subsequently are homogenized in a stainless-steel container for 10 min. The resulting mixture is poured into the reservoir of a POLYLAB OS Thermofisher hot melt extruder. The mixture is continuously dosed to a worm transporter, where it gradually passes from the filling section through heated sections, where mixing, compression and melting of the polymer takes place. The process temperature is 140°C. At the end of the worm transporter the melted mixture is extruded through openings (of a matrix) out of the extruder. After cooling with air and solidification, the extrudate is ground with the use of rotating knives (rough grinding). The resulting roughly ground extrudate is further refined to the defined particle size in the next grinder; see Example 1 - fine grinding. The finely ground extrudate is used for the next production step, where auxiliary substances are gradually sieved in several steps (through a 1.0mm sieve) and mixed with the extrudate containing agomelatine in such a way that a sufficiently homogeneous mixture of substances for tableting results. The cores are coated with a suspension consisting of common excipients.

Composition of the product - core

Particle size of the extrudate measured by sieve analysis (agomelatine and Kollidon VA64 the weight ratio of 15 : 85)

Particle fraction (mm) Rough grinding Fine grinding

Over 1.6 2.2 0

1.4 - 1.6 3.4 0.4

No crystalline form of agomelatine was detected in the ground extrudate in accordance with Example 1 or in the cores made from this extrudate (see Figs. 1 and 2). The dissolution profile was faster than that of the reference product (see Fig. 10). The solid solution in the cores made from this extrudate was stable at 25°C and 60% relative humidity for 6 months, as well as at 40°C and 75% relative humidity for 6 months.

EXAMPLE 2

The same procedure as in Example 1 is followed. The only difference is in the composition- Agomelatine and Kollidon VA64 in the weight ratio of 30 : 70. The process temperature is 120°C.

Composition of the product - core

Particle size of the extrudate measured by sieve analysis (agomelatine and Kollidon VA64 in the weight ratio of 30 : 70)

No crystalline form of agomelatine was detected in the ground extrudate in accordance with Example 2 or in the cores made from this extrudate (see fig. 3 and 4). The dissolution profile was faster than the dissolution profile of the reference preparation (see fig. 10). The solid solution in cores made from this extrudate was stable for 6 months at 25 °C and 60% relative humidity as well as for 6 months at 40°C and 75% relative humidity.

EXAMPLE 3

The same procedure as in Example 1 or 2 is followed. The composition is the same as in Example 2 - Agomelatine and Kollidon VA64 in the weight ratio of 30 : 70;the process temperature is 135°C. The only difference is in the particle size of the ground extrudate - grinding to finer particles than in Example 1 or 2.

Composition of the product - core

Substance Amount/core Specification

(mg)

Extrudate 83.33

- Agomelatine (30%) - 25.00 In-house

- Kollidon VA64 (70%) - 58.33 Ph. Eur.

No admixture of a crystalline form of agomelatine was detected in the ground extrudate in accordance with Example 3 (see Fig. 5). This example has been evaluated as acceptable.

EXAMPLE 4

The same procedure as in Example 1 or 2 is followed. The only difference is the composition - Agomelatine and Kollidon VA64 in the weight ratio of 45 : 55. The process temperature is 120°C.

Composition of the product - core

- Kollidon VA64 (55%) - 30.56 PLEur.

Macrocrystalline cellulose 59.67 Ph.Eur.

Colloidal silicon dioxide 2.00 Ph.Eur.

Crosspovidone 30.00 Ph.Eur.

Stearic acid 3.00 Ph.Eur.

Magnesium stearate 2.00 Ph.Eur.

Total weight of the core 152.23 mg —

Particle size of the extrudate measured by sieve analysis (agomelatine and Kollidon VA64 in the weight ratio of 45 : 55)

No admixture of a crystalline form of agomelatine was detected in the ground extrudate in accordance with Example 4 (see Fig. 6). At the concentration of 45% of agomelatine in the extrudate absence of the crystalline form of agomelatine in the extrudate can be achieved; this is an acceptable example.

EXAMPLE 5 - COMPARATIVE

The same procedure as in Example 1 or 2 is followed. The composition is the same as in Example 2 - Agomelatine and Kollidon VA64 in the weight ratio of 30 : 70. The process temperature is 120°C. The only difference is in the particle size of the ground extrudate - grinding to very fine particles, 77% of weight of extrudate particles are smaller than 0.1 mm. Composition of the product - core

Admixed crystalline Form II of agomelatine was detected in the ground extrudate in accordance with Example 5 (see Fig. 7). Due to unsuitable polymorphy the dissolution profile was not measured. EXAMPLE 6 - COMPARATIVE

The same procedure as in Example 1 or 2 is followed. The only difference is in the composition- Agomelatine and Kollidon VA64 in the weight ratio of 50 : 50 - see Example 2. The process temperature is 120°C.

Composition of the product - core

Particle size of the extrudate measured by sieve analysis (agomelatine and Kollidon VA64 in the weight ratio of 50 : 50)

Admixed crystalline Form II of agomelatine was detected in the ground extrudate in accordance with Example 6 (see Fig. 8). At the concentration of 50% of agomelatine in the extrudate absence of the crystalline form of agomelatine in the extrudate cannot be achieved. Due to unsuitable polymorphy the dissolution profile was not measured.

EXAMPLE 7 - COMPARATIVE Agomelatine and Soluplus in the weight ratio of 30 : 70 are sieved through a 1.0 mm sieve and subsequently homogenized in a stainless-steel container for 10 min. The resulting mixture is poured into the reservoir of a POLYLAB OS Thermofisher hot melt extruder. The mixture is continuously dosed to a worm transporter, where it gradually passes from the filling section through heated sections, where mixing, compression and melting of the polymer takes place. The process temperature is 120°C.

At the end of the worm transporter the melted mixture is extruded through openings (of a matrix) out of the extruder. After cooling with air and solidification, the extrudate is ground with the use of rotating knives. The resulting roughly ground extrudate is further refined in the next grinder to the defined particle size, see Example 1 - fine grinding. The finely ground extrudate is used for the next production step, where auxiliary substances are gradually sieved (through a 1.0mm sieve) in several steps and mixed with the extrudate containing agomelatine in such a way that a sufficiently homogeneous mixture of substances for tableting results. The cores are coated with suspension consisting of common excipients, see Example 1.

Composition of the product - core

Particle size of the extrudate measured by sieve analysis (agomelatine and Soluplus in the weight ratio of 30 : 70)

No admixture of a crystalline form of agomelatine was detected in the roughly ground extrudate in accordance with Example 7. However, this particle size is not suitable for use in pharmaceutical formulations. Presence of a crystalline form of agomelatine was detected in the finely ground extrudate in accordance with Example 7 as well as in the cores made from this extrudate (see Fig. 9). The dissolution profile of this formulation containing a solid dispersion of agomelatine was considerably slower than that of the reference product (see Fig. 10).

Claims

1. A thermodynamically stable solid solution of agomelatine for use in a pharmaceutical composition, characterized in that it contains agomelatine (N-[2-(7-methoxy-1- naphtyl)ethyl] acetamide) of formula I

dissolved in a polymeric carrier, wherein

■ the polymeric carrier is a copolymer of polyvinylpyrrolidone with polyvinyl acetate in the weight ratio of 3 :2,

■ the concentration of agomelatine in the polymeric carrier is up to 45% of weight, related to the weight of said solid solution, and " at most 60% by weight of the particles of said solid solution are smaller than 0.1 mm.

2. The thermodynamically stable solid solution of agomelatine in accordance with claim 1, characterized in that the concentration of agomelatine in the solid solution is 15 to 30% by weight.

3. The thermodynamically stable solid solution of agomelatine in accordance with claim 1, characterized in that the weight ratio of agomelatine to the polymeric carrier is lower than 1 :

1.2.

4. The thermodynamically stable solid solution of agomelatine in accordance with claim 3,

■ characterized in that the weight ratio of agomelatine to the polymeric carrier is in the range of 1 : 1.2 to 1: 5.7.

5. The thermodynamically stable solid solution of agomelatine in accordance with any one of the preceding claims, characterized in that at most 53% by weight of the particles of the solid solution are smaller than 0.1 mm.

6. The thermodynamically stable solid solution of agomelatine in accordance with any one of the preceding_claims, characterized in that at least 20% by weight of the particles are smaller than 100 micrometers, at least 70% by weight of the particles are smaller than 500 micrometers and at least 90% by weight of the particles are smaller than 1000 micrometers.

7. A process for the preparation of the thermodynamically stable solid solution of agomelatine in accordance with claims 1 to 6, characterized in that said solid solution is prepared using the hot melt extrusion method and subsequent grinding of the resulting extrudate.

8. The process in accordance with claim 7, characterized in that said solid solution is prepared using a process comprising the following steps: a/ mixing and homogenizing agomelatine with the polymeric carrier, which is a copolymer of poly vinylpyrrolidone with polyvinyl acetate in the weight ratio of 3:2, in a weight ratio of agomelatine to the polymeric carrier lower than 1 : 1.2;

b/ heating the mixture after or during step a/ to a temperature sufficient to melt the mixture; and

c/ subsequently cooling the mixture to a temperature lower than its melting point, performed during the extrusion process.

9. The process in accordance with claim 8, characterized in that agomelatine used as the starting material is in the crystalline Form I.

10. The process in accordance with claims 8 or 9, characterized in that a temperature in the range of 120 - 140°C is used to melt the mixture of agomelatine with the polymeric carrier.

11. The process in accordance with claim 10, characterized in that the temperature of 120°C is used to melt the mixture of agomelatine with the polymeric carrier.

12. A pharmaceutical composition for oral administration, characterized in that it contains a mermodynamically stable solid solution of agomelatine in accordance with claims 1 to 6, prepared by a process in accordance with claims 7 to 11, and non-hygroscopic pharmaceutically acceptable auxiliary substances with the free water content lower than 7% by weight

13. The pharmaceutical composition in accordance with claim 12, characterized in that the particle size distribution of said solid solution of agomelatine is such that at least 20% by weight of the particles are smaller than 100 micrometers, at least 70% by weight of the particles are smaller than 500 micrometers and at least 90% by weight of the particles are smaller than 1000 micrometers.

14. The pharmaceutical composition in accordance with claim 13, characterized in that the auxiliary substances are fillers, disintegrants, binders and/or lubricants.

15. The pharmaceutical composition in accordance with claim 14, characterized in that the filler is microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, lactose monohydrate, mannitol and/or sorbitol.

16. The pharmaceutical composition in accordance with claim 15, characterized in that the filler is microcrystalline cellulose with a water content of up to 1.5% by weight.

17. The pharmaceutical composition in accordance with claim 14, characterized in that the disintegrant is crosspovidone, low substituted hydroxypropyl cellulose and/or colloidal silicon dioxide.

18. The pharmaceutical composition in accordance with claim 14, characterized in that the binder polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose and/or hydroxyethyl cellulose.

19. The pharmaceutical composition in accordance with claim 14, characterized in that the lubricant magnesium stearate, calcium stearate, stearic acid and/or sodium stearyl fumarate.

20. The pharmaceutical composition in accordance with claims 12-19, characterized in that it is in the form of tablets.

21. The pharmaceutical composition in accordance with claim 21, characterized in that it is in the form of coated tablets.

22. A process for the manufacture of a pharmaceutical composition in accordance with claims 12 to 21, characterized in that a stable solid solution of agomelatine in accordance with claims 7 to 11 is prepared, to which non-hygroscopic pharmaceutically acceptable auxiliary substances with a lower content of free water than 7% by weight are further added, wherein said mixture is processed by dry granulation.

23. A process for the manufacture of a pharmaceutical composition in accordance with claims 12 to 21, characterized in that a stable solid solution of agomelatine in accordance with claims 7 to 11 is prepared, to which non-hygroscopic pharmaceutically ^"acceptable^' auxiliary-— substances with a lower content of free water than 7% by weight are further added, wherein said mixture is processed by direct tabletting.