CZ2013621A3 - Agomelatine thermodynamically stable congealed solution for use in pharmaceutical formulation - Google Patents

Abstract

The subject of the invention is a thermodynamically stable agomelatine-containing solid solution containing agomelatine dissolved in a polymeric carrier, which is a polyvinylpyrrolidone-polyvinyl acetate copolymer in a 3: 2 weight ratio, its production method and are pharmaceutical compositions containing agomelatine (N- [2- (7-methoxy-1 -naphthyl) ethyl] acetamide) of formula (I) and a process for their preparation.

Description

THERMODYNAMICALLY STABLE AGOMELATIN SOLID SOLUTION FOR

USE IN PHARMACEUTICAL FORMULATION

Field of technology

The subject of the invention are pharmaceutical compositions containing a solid solution of agomelatine (N[2-(7-methoxy-1-naphthyl)ethyl]acetamide) of the formula (I) and a process for their preparation.

Current state of the art

Preparations containing agomelatine belong to the group of antidepressant drugs. Agomelatine is a melatoninergic agonist (MTi and MT ₂ receptors) and an antagonist of serotoninergic 5-HT ₂ c receptors.

Agomelatine was first disclosed in EP 0 447 285 (Adir et Compagnie). There are a number of polymorphic forms of agomelatine. E.g. in the application WO2005077887 (Servier) the form II of agomelatine is described, in the application WO2007015003 (Servier) the form III of agomelatine, in the application WO2007015002 (Servier) the form IV of agomelatine, in the application WO2007015004 (Servier) the form V of agomelatine, in the application WO2009095555 (Servier) the form VI agomelatine and in application WO2011006387 (Zhejiang Huahai Pharmaceutical Co., Ltd.) forms A, B, and C of agomelatine.

Of these polymorphic forms, form II is the most permanent. During the production and storage of preparations containing agomelatine in a polymorphic form other than form II, sooner or later the transformation of another form or forms into the thermodynamically more stable form II usually occurs.

Agomelatine is available on the market in two preparations (Valdoxan and Thymanax, both 25 mg strength) by Servier. In these preparations, agomelatine is in polymorphic form II.

Pharmacokinetic studies have shown that the bioavailability of agomelatine when administered orally is very low compared to parenteral administration and is highly variable when administered to different patients (interindividual variability) and when repeated administration of agomelatine to the same patient (intraindividual variability).

Problems with the bioavailability and variability of immediate-release pharmaceutical formulations of agomelatine have led to a search for formulations that overcome these problems.

It is a well-known fact from the literature that the solubility, and thus the dissolution, i.e. the bioavailability of substances poorly soluble in water can be increased by converting them into a solid solution.

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

When preparing solid solutions according to these recommendations, however, the authors of the present invention failed to prepare a true solid solution without detectable particles of agomelatine. Instead, a solid dispersion was formed, either directly after production or later during stability testing by recrystallization of agomelatine.

In the end, the authors of the invention managed to find parameters that influence the resulting state of the material - whether it will be in the form of a solid solution or a solid dispersion not only immediately after production, but also after processing into a pharmaceutical formulation throughout the stability testing period.

The present invention provides bioavailable pharmaceutical compositions containing a thermodynamically stable solid solution of agomelatine, which provide a uniform release of agomelatine, guarantee a suitable dissolution profile and do not cause unwanted recrystallization of agomelatine.

The essence of the invention

The essence of the invention is a thermodynamically stable solid solution of agomelatine for use in a pharmaceutical formulation with a concentration of agomelatine in a polymer carrier of up to 45% by weight, based on the weight of the solid solution, whose particle size distribution after grinding is such that a maximum of 60% by weight particles smaller than 0.1 mm. The polymer carrier used is a copolymer of polyvinylpyrrolidone with polyvinyl acetate (copovidone) in a weight ratio of 3:2 (Kollidon VA64). A pharmaceutical composition comprising this stable solid solution of agomelatine and non-hygroscopic pharmaceutically acceptable excipients with a low water content is also claimed. Both these solid solutions and pharmaceutical compositions are thermodynamically stable, which was confirmed by stability testing under various conditions (natural and accelerated stability) and satisfactory in terms of dissolution profiles.

Detailed description of the invention

The subject of the invention are thermodynamically stable solid solutions of agomelatine for use in a pharmaceutical formulation with a concentration of agomelatine in a polymer carrier of up to 45% by weight, based on the weight of the solid solution, whose particle size distribution after grinding is such that it is a maximum of 60% by weight. particles smaller than 0.1 mm, while the polymer carrier used is a copolymer of polyvinylpyrrolidone with polyvinyl acetate (copovidone) in a weight ratio of 3:2 (Kollidon VA64). Furthermore, the subject of this invention are pharmaceutical formulations containing this solid solution, the advantage of which is their faster and better solubility than the solubility of the agomelatine reference preparation containing agomelatine particles (see Figure 10).

A solid solution of agomelatine and such a polymer carrier is thermodynamically stable and does not cause unwanted recrystallization of agomelatine. Compositions containing a solid solution of agomelatine and a polymeric carrier according to the present invention are faster and more soluble than the reference preparation of agomelatine.

For the preparation of a solid solution of agomelatine, all information available in the BASF material Hot Melt Extrusion with BASF Pharma Polymers Extrusion Compendium, August, 2010, was first used, which describes the preparation of solid solutions of poorly soluble substances (including 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 ground solid solution is used for the preparation of pharmaceutical compositions.

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

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

It was therefore necessary to further search for suitable conditions given by a combination of optimal parameters, in which recrystallization did not occur during the solidification process of the melt, during the storage of the solid solution, or during the preparation and storage of the pharmaceutical composition. The parameters essential for achieving the technical effect of the invention are the type of polymer carrier, the concentration of agomelatine in this polymer carrier and the particle size of the ground solid solution. On the other hand, the parameters that proved to be insignificant for achieving the technical effect of the invention are, for example, the temperature of the process (any melting temperature can be used in the range where the active substance and polymer melt reliably and when the active substance does not degrade at the same time), the cooling rate, type of equipment for preparing a solid solution, method of grinding the solid solution (three types of equipment were tested), etc.

"Solid solution" means a chemically and physically homogeneous amorphous material in which the molecules of the dissolved substance are homogeneously dispersed between the molecules of the carrier substance (substances forming the matrix of the solid solution) and in which the particles of the dissolved substance are not detectable by any method known from the state of the art (e.g. optical and electron microscope, FTIR microscopy, X-ray analysis, NMR).

"Solid dispersion" means a chemically and physically inhomogeneous material in which particles of a dissolved substance can be detected by a method known from the state of the art (e.g. optical and electron microscope, FTIR microscopy, X-ray analysis, NMR).

Concentration of agomelatine in solid solution

The concentration of agomelatine in the solid solution according to the invention, which consists of agomelatine dissolved in a polymer carrier, can be up to 45% by weight, preferably 15 to 30% by weight, based on the weight of the solid solution.

In a preferred solution, the concentration of agomelatine in the solid solution is 15% by weight, based on the weight of the solid solution. In another preferred solution, the agomelatine concentration in the solid solution is 30% by weight, based on the weight of the solid solution.

The ratio of agomelatine to the polymer carrier in the solid solution according to the invention is lower than 1:1.2 (by weight), preferably from 1:1.2 to 1:5.7 (by weight).

Polymer carrier

The polymer carriers listed in the BASF document as preferred were tested, i.e. Kollidon VA-64 (a copolymer of polyvinylpyrrolidone with polyvinyl acetate (copovidone) in a weight ratio of 3:2), Soluplus (a copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol) and Kollidon 30 (polyvinylpyrrolidone with a molecular weight characterized by K 30).

The use of Kollidon 30 (polyvinylpyrrolidone with a molecular weight characterized by K 30) proved to be possible but disadvantageous. The glass transition temperature (Tg) of Kollidon 30 is 149°C and the working temperature is 20°C higher, while the melting point of agomelatine is around 100°C. For the preparation of solid solutions, it is optimal for the active substance and the polymer carrier to have close melting temperatures, which is not fulfilled here, although it was possible to prepare a solid solution of agomelatine. However, the higher melting point of Kollidon 30 means higher energy costs and therefore no further stability or dissolution tests were performed.

Soluplus turned out to be completely unsuitable for the preparation of a solid solution of agomelatine. When using a copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol (Soluplus), crystalline form II of agomelatine was always at least partially detected in the extrudate, and crystalline form II was detected immediately after production in the final medicinal form (coated tablets) as well (see comparative Example 3 ). With this polymer, it was not possible to find conditions under which it would be possible to prepare a stable solid solution without admixture of recrystallized dispersed particles of agomelatine.

The preferred polymer carrier for this technical solution is a copolymer of polyvinylpyrrolidone with polyvinyl acetate (Kollidon VA64). The use of Kollidon VA64, while observing the other parameters discussed, led to the formation of a stable form of both the extrudate with a coarser particle size, the extrudate after grinding to a fine particle size, and the final medicinal form after production and during storage of the wrapped tablets for 1 month at 40 °C and 75 % relative humidity. From the point of view of XRPD analysis, it is a confirmation of the absence of the crystalline form in the sample.

Particle size of a solid solution

Very surprising was the observation that the stability of the solid solution has a very significant effect on the size of the particles to which the solid solution is ground for use in pharmaceutical formulations. If the solid solution was ground too finely, gradual recrystallization occurred immediately during grinding or even gradually during stability testing into an undesirable solid dispersion, which, however, showed very poor dissolution profiles when used in pharmaceutical formulations.

It was found that in order to ensure the stability of the solid solution and to prevent recrystallization of agomelatine from a solid solution to a solid dispersion, it is necessary that, after grinding, a maximum of 60% by weight solid solution particles smaller than 0.1 mm.

From the point of view of using a solid solution in a pharmaceutical formulation and ensuring favorable dissolution profiles, it is then advantageous that at least 20 wt.% of ground extrudate particles smaller than 100 micrometers, at least 70 wt.% particles of the ground extrudate were smaller than 500 micrometers and at least 90 wt.% particles of ground extrudate smaller than 1000 micrometers.

Pharmaceutical formulations containing a solid solution of agomelatine

Another aspect of the present invention are pharmaceutical compositions containing a solid solution of agomelatine and pharmaceutically acceptable excipients, e.g. fillers, disintegrants, binders and/or lubricants.

Preferred excipients are those that have a low free water content (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. The preferred filler is microcrystalline cellulose, especially microcrystalline cellulose with a water content of up to 1.5% by weight. (e.g. type Avicel PH112).

Crospovidone, low-substituted hydroxypropyl cellulose and/or colloidal silicon dioxide can be used as disintegrants. Crospovidone and silicon dioxide are preferred, and a combination of these two disintegrants is particularly 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. The preferred solution is to use a combination of magnesium stearate and stearic acid.

The pharmaceutical formulations may be prepared in any commonly used form for oral administration, e.g. in the form of capsules, tablets or coated tablets, and may be packaged e.g. in bottles or blisters of foil containing a layer of PVC, a layer of PE and a layer of PVDC sealed with aluminum foil (so-called PVC/PE/PVDC//ALU blisters) or into aluminum foil blisters closed with aluminum foil (so-called ALU//ALU blisters), in a normal or inert atmosphere. Normal atmosphere is air, inert atmosphere is gas with an oxygen content of less than 21% by volume. An inert atmosphere is preferably made up of at least 95% by volume of nitrogen or 95% by volume of argon.

Preparation of solid solutions

Solid solutions of agomelatine and the polymer carrier according to the invention can be prepared using hot melt extrusion (HME) technology.

This involves heating a pre-homogenized mixture of agomelatine and a polymer carrier, and possibly other auxiliary substances, to a suitable temperature at which agomelatine can be dissolved in the molten polymer carrier. In the preferred solution, agomelatine of crystalline form I is used as the starting material. The temperature of the process must not be too high to prevent chemical decomposition of the active substance, but high enough to form a clear solution of the active substance in the polymer carrier.

For the preferred copolymer of polyvinylpyrrolidone with polyvinyl acetate in a weight ratio of 3:2 (Kollidon VA64), the optimum temperature of 120°C to 140°C was verified. This was confirmed by XRPD analysis, which showed the absence of a crystalline form. At lower temperatures, e.g. 95 °C or 110 °C, a solid dispersion of agomelatine was formed, not a solid solution. It is particularly advantageous, from an economic point of view, to use a melting temperature of 120°C.

During the extrusion process, after dissolving agomelatine in the polymer, the resulting mixture is gradually pushed through a matrix of a suitable size, e.g. 3-6 mm, and then cooled with air. After cooling and solidification, the resulting extrudate is ground into small pieces with a rotating knife or other technique and is ready for further processing.

Extrudate production is verified on two types of extruders (Thermofisher, ThreeTec). The amount of extrudate produced per hour is tested up to 1 kg/hour and the torque of the extruder force was 35-125 N.m.

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

Preparation of pharmaceutical formulations

During the preparation of the pharmaceutical composition containing a solid solution of agomelatine, due to the properties of the active substance, technologies were used excluding the solvent (e.g. water or ethanol). This is direct tableting technology or dry granulation technology.

Direct tableting is a technological process where, in several steps, excipients are sifted and mixed with an extrudate containing agomelatine so that the result is a sufficiently homogeneous mixture of substances for tableting. The cores are coated with a suspension made up of common excipients. The direct tableting process is advantageous in its simplicity.

An alternative technology can be dry granulation, e.g. compaction. Compaction means a production method where the extrudate containing agomelatine and other excipients are homogenized in one or several production steps, then a strip of compact material is pressed out under the action of pressure in the compactor, which is then ground on a sieving device to a defined particle size according to the mesh size of the sieve. The resulting granulate is either used directly for the production of tablets, or one or more excipients are mixed with it and then used for the production of cores or tablets. The cores are coated with a suspension made up of common excipients.

The next stage of production is tableting and then coating and adjusting the tablets.

A more detailed embodiment of the process according to the invention is indicated in the Examples.

Overview of images on the drawings

Giant. 1: XRPD analysis - confirmation of the absence of the crystalline form of agomelatine in the extrudate of example 1 (1- coarsely ground extrudate, 2 - finely ground, 3 - the polymer collidon VA64 itself, 4 - comparative: agomelatine of crystalline form I)

Giant. 2: XRPD analysis - confirmation of the absence of the crystalline form of agomelatine in the cores made from the extrudate from example 1 (1 - finely ground extrudate, 2 - cores from this extrudate, 3 - verification of the presence of magnesium stearate in the cores)

Giant. 3: XRPD analysis - confirmation of the absence of the agomelatine crystalline form in the extrudate of example 2 (1 - coarsely ground extrudate, 2 - finely ground, 3 comparative: agomelatine crystalline form II)

Giant. 4: XRPD analysis - confirmation of the absence of the crystalline form of agomelatine in the cores made from the extrudate from example 2 (1- finely ground extrudate, 2 - cores from this extrudate, 3 - verification of the presence of magnesium stearate, 4 - verification of the presence of stearic acid in the cores)

Giant. 5: XRPD analysis - confirmation of the absence of the crystalline form of agomelatine in the extrudate of example 3 (1 - finely ground extrudate, 2 - the Kollidon VA64 polymer itself, 3 - comparative: agomelatine of the crystalline form I)

Giant. 6: XRPD analysis - confirmation of the absence of the crystalline form of agomelatine in the extrudate of example 4 (1 - finely ground extrudate, 2 - the Kollidon VA64 polymer itself, 3 - comparative: agomelatine of the crystalline form I)

Giant. 7: XRPD analysis - confirmation of the absence of the crystalline form of agomelatine in the extrudate of example 5 (1 - finely ground extrudate, 2 - comparative: agomelatine of crystalline form II)

Giant. 8: XRPD analysis - confirmation of the absence of the crystalline form of agomelatine in the extrudate of example 6 (1 - finely ground extrudate, 2 - comparative: agomelatine of crystalline form II)

Giant. 9: XRPD analysis - proof of the presence of a mixture of crystalline form II in the finely ground extrudate in example 7 (1- coarsely ground extrudate, 2 - finely ground extrudate, 3 - comparative: agomelatine of crystalline form II)

Giant. 10: Dissolution profds

- example 1 (batch 230611), 2 - example 2 (batch 200511), 3 - example 7 (batch 210511), 4 reference product (for batch 200511 - example 2 and even more for batch 230611 - example 1 these are solid solutions , faster dissolution profiles are observed compared to the reference preparation; on the contrary, batch 210511 - example 7 is a solid dispersion and there is a significant slowing down of the dissolution profile compared to the reference preparation)

Examples of embodiments of the invention

Example Polymer carrier Ratio ago : poles* % mass <0.1 mm ** melting point 1 Kollidon VA-64 15:85 48% 140°C 2 Kollidon VA-64 30:70 51% 120 °C 3 Kollidon VA-64 30:70 60% 135°C 4 Kollidon VA-64 45:55 50% 120 °C 5 - comparative Kollidon VA-64 30:70 77% 120 °C 6 - comparative Kollidon VA-64 50:50 52% 120 °C 7 - comparative Soluplus 30:70 23% 120 °C

* ratio of agomelatine to polymer carrier ** % wt. of extrudate particles smaller than 0.1 mm

EXAMPLE 1

Agomelatine and Kollidon VA64 in a mass ratio of 15:85 are sieved through a 1.0 mm sieve and then homogenized for 10 min in a stainless steel container. The resulting mixture is poured into the hot melt reservoir of the POLYLAB OS Thermofisher extruder. The mixture is continuously dosed into the screw conveyor, where it gradually passes from the filling section through the heated sections, in which mixing, compression and melting of the polymer take place. The process temperature is 140 °C. At the end of the screw conveyor, the molten mixture is pushed through the holes (die) out of the extruder. After cooling with air and solidification of the extrudate, it is ground using rotating knives (coarse grinding). The resulting coarsely ground extrudate is further refined on another grinder to a defined particle size, see example 1 - fine grinding. The finely ground extrudate is used for the next stage of production, where the excipients are gradually sieved (through a 1.0 mm sieve) in several steps and mixed with the extrudate containing agomelatine so that the result is a sufficiently homogeneous mixture of substances for tableting. The cores are coated with a suspension made up of common excipients.

Product composition - cores

Substance Quantity/kernel (mg) Specifications Extrudate Agomelatine (15%) - Kollidon VA64 (85%) 166.67 - 25.00 - 141.67 In-house Ph.Eur. Microcrystalline cellulose 109.94 Ph.Eur. Colloidal silicon dioxide 2.00 Ph.Eur. Ph.Eur.___________________

Crospovidone 66.38

Stearic acid 3.00 Ph.Eur. Magnesium stearate 2.00 Ph.Eur. Total core weight 350 mg

Extrudate particle size measured by sieve analysis (agomelatine and collidon VA64 in a weight ratio of 15 : 85)

Particle fraction (mm) It grinds coarsely It grinds finely Above 1.6 2.2 0 1.4-1.6 3.4 0.4 1.25-1.4 72.2 1.2 1.0-1.25 15.2 1.2 0.8-1.0 2.4 0.4 0.5-0.8 2.4 1.2 0.25 - 0.5 1.4 5.8 0.125-0.25 0.2 21.6 0.1 - 0.125 0 19.6 Below 0.1 0 47.6

The crystalline form of agomelatine was not detected in the ground extrudate according to Example 1 or in the cores made from this extrudate (see Figs. 1 and 2). 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% RH and for 6 months at 40°C and 75% RH.

EXAMPLE 2

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

Product composition - cores

Substance Quantity/kernel (mg) Specifications Extrudate Agomelatine (30%) - Kollidon VA64 (70%) 83.33 - 25.00 - 58.33 In-house Ph.Eur. Microcrystalline cellulose 59.67 Ph.Eur. Colloidal silicon dioxide 2.00 Ph.Eur. Crospovidone 30.00 Ph.Eur. Stearic acid 3.00 Ph.Eur. Magnesium stearate 2.00 Ph.Eur. Total core weight 180 mg --

Extrudate particle size measured by sieve analysis (agomelatine and collidon VA64 in a mass ratio of 30 : 70)

Particle fraction (mm) Coarse grinding (wt% fraction) Fine grinding (wt% fraction) Above 1.6 1.5 0.1 1.4-1.6 3.1 0.6 1.25-1.4 68.4 1.5 1.0-1.25 15.3 1.4 0.8-1.0 3.9 1.2 0.5-0.8 5.1 3.4 0.25-0.5 2.1 5.3 0.125-0.25 0.5 18.1 0.1 - 0.125 0.1 17.3 Below 0.1 0 51.1

The crystalline form of agomelatine was not detected in the ground extrudate according to Example 2 or in the cores made from this extrudate (see Figs. 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% RH and for 6 months at 40°C and 75% RH.

EXAMPLE 3

The procedure is the same as in example 1 or 2. The composition is the same as in example 2 - Agomelatine and collidon VA64 in a mass ratio of 30:70, the process temperature is 135 °C. The particle size of the ground extrudate is different - grinding into finer particles than in example 1 or 2.

Product composition - cores

Substance Quantity/kernel (mg) Specifications Extrudate Agomelatine (30%) - Kollidon VA64 (70%) 83.33 - 25.00 - 58.33 In-house Ph.Eur. Microcrystalline cellulose 59.67 Ph.Eur. Colloidal silicon dioxide 2.00 Ph.Eur. Crospovidone 30.00 Ph.Eur. Stearic acid 3.00 Ph.Eur. Magnesium stearate 2.00 Ph.Eur. Total core weight 180 mg —

Extrudate particle size measured by sieve analysis (agomelatine and collidon VA64 in a mass ratio of 30 : 70)

Particle fraction (mm) Coarse grinding (wt% fraction) Grinding into finer particles (wt% fraction) Above 1.6 1.5 0 1.4-1.6 3.1 0 1.25-1.4 68.4 0 1.0-1.25 15.3 0.1 0.8-1.0 3.9 0.2 0.5-0.8 5.1 0.6 0.25-0.5 2.1 4.1 0.125-0.25 0.5 13.6 0.1 - 0.125 0.1 21.6 Below 0.1 0 59.8

In the ground extrudate according to example 3, no admixture of the crystalline form of agomelatine was detected (see Fig. 5). This example has been evaluated as satisfactory.

EXAMPLE 4

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

Product composition - cores

Substance Quantity/kernel (mg) Specifications Extrudate Agomelatine (45%) - Kollidon VA64 (55%) 55,56 - 25.00 - 30.56 In-house Ph.Eur. Microcrystalline cellulose 59.67 Ph.Eur. Colloidal silicon dioxide 2.00 Ph.Eur. Crospovidone 30.00 Ph.Eur. Stearic acid 3.00 Ph.Eur. Magnesium stearate 2.00 Ph.Eur. Total core weight 152.23 mg —

Extrudate particle size measured by sieve analysis (agomelatine and collidon VA64 in a mass ratio of 45 : 55)

Particle fraction (mm) Coarse grinding (wt% fraction) Fine grinding (wt% fraction) Above 1.6 0.9 0 1.4-1.6 2.2 0.2 1.25-1.4 65.8 1.3

1.0-1.25 19.2 2 0.8-1.0 4 1.7 0.5-0.8 4.9 3.8 0.25-0.5 1.9 5 0.125-0.25 0.8 15.3 0.1 - 0.125 0.2 19.8 Below 0.1 0.1 50.9

In the ground extrudate according to example 4, no admixture of the crystalline form of agomelatine was detected (see Fig. 6). At a concentration of 45% agomelatine in the extrudate, it is possible to achieve the absence of the crystalline form of agomelatine in the extrudate, this is a satisfactory example.

EXAMPLE 5 - COMPARATIVE

The procedure is the same as in example 1 or 2. The composition is the same as in example 2 - Agomelatine and Kollidon VA64 in a weight ratio of 30:70. The process temperature is 120 °C. The size of the particles of the ground extrudate is different - grinding into very fine particles, 77% of the mass, the particles of the extrudate are smaller than 0.1 mm.

Product composition - cores

Substance Quantity/kernel (mg) Specifications Extrudate Agomelatine (30%) - Kollidon VA64 (70%) 83.33 - 25.00 - 58.33 In-house Ph.Eur. Microcrystalline cellulose 59.67 Ph.Eur. Colloidal silicon dioxide 2.00 Ph.Eur. Crospovidone 30.00 Ph.Eur. Stearic acid 3.00 Ph.Eur. Magnesium stearate 2.00 Ph.Eur. Total core weight 180 mg —

Extrudate particle size measured by sieve analysis (agomelatine and collidon VA64 in a mass ratio of 30 : 70)

Particle fraction (mm) Coarse grinding (wt% fraction) Very fine grinding (wt.% fraction) Above 1.6 1.1 0 1.4-1.6 3.9 0 1.25-1.4 65.8 0 1.0-1.25 16.1 0 0.8-1.0 4.4 0.1 0.5-0.8 5.4 0.5 0.25-0.5 1.9 2 0.125-0.25 0.8 5.9

0.1-0.125 0.4 14.2 Below 0.1 0.2 77.3

An admixture of crystalline form II of agomelatine was detected in the ground extrudate according to example 5 (see Fig. 7). Due to unsatisfactory polymorphism, the dissolution profile was not measured either.

EXAMPLE 6 - COMPARATIVE

The procedure is the same as in example 1 or 2. The only difference is the composition - Agomelatine and collidon VA64 in a weight ratio of 50:50 - see example 2. The processing temperature is 120 °C.

Product composition - cores

Substance Quantity/kernel (mg) Specifications Extrudate Agomelatine (45%) - Kollidon VA64 (55%) 50.00 - 25.00 - 25.00 In-house Ph.Eur. Microcrystalline cellulose 59.67 Ph.Eur. Colloidal silicon dioxide 2.00 Ph.Eur. Crospovidone 30.00 Ph.Eur. Stearic acid 3.00 Ph.Eur. Magnesium stearate 2.00 Ph.Eur. Total core weight 146.67 mg --

Extrudate particle size measured by sieve analysis (agomelatine and Kollidon VA64 in a weight ratio of 50 : 50)

Particle fraction (mm) Coarse grinding (wt% fraction) Fine grinding (wt% fraction) Above 1.6 1.1 0 1.4-1.6 2.6 0.4 1.25-1.4 65.2 1.2 1.0-1.25 18.9 1.6 0.8-1.0 4.5 1.5 0.5-0.8 4.7 4 0.25 - 0.5 L5 5.2 0.125-0.25 1.1 16 0.1-0.125 0.3 18.1 Below 0.1 0.1 52

An admixture of crystalline form II of agomelatine was detected in the ground extrudate according to example 6 (see Fig. 8). At a concentration of 50% agomelatine in the extrudate, it is not possible to achieve the absence of the crystalline form of agomelatine in the extrudate. Due to unsatisfactory polymorphism, the dissolution profile was not measured either.

EXAMPLE 7 - COMPARATIVE

Agomelatine and Soluplus in a weight ratio of 30:70 are sifted through a 1.0 mm sieve and then homogenized for 10 minutes in a stainless steel container. The resulting mixture is poured into the hot melt reservoir of the POLYLAB OS Thermofisher extruder. The mixture is continuously dosed into the screw conveyor, where it gradually passes from the filling section through the heated sections, in which mixing, compression and melting of the polymer take place. The processing temperature is 120 °C.

At the end of the screw conveyor, the molten mixture is pushed through the holes (die) out of the extruder. After cooling with air and solidification of the extrudate, it is ground using rotating knives. The resulting coarsely ground extrudate is further refined on another grinder to a defined particle size, see example 1 - fine grinding. The finely ground extrudate is used for the next stage of production, when it is gradually sifted (through a 1.0 nim sieve) and mixed with the extrudate containing agomelatine in several steps, so that the result is a sufficiently homogeneous mixture of substances for tableting. The cores are coated with a suspension consisting of common excipients, see example 1.

Product composition - cores

Substance Quantity/kernel (mg) Specifications Extrudate Agomelatine (30%) - Soluplus (70%) 83.33 - 25.00 - 58.33 In-house In-house Microcrystalline cellulose 59.67 Ph.Eur. Colloidal silicon dioxide 2.00 Ph.Eur. Crospovidone 30.00 Ph.Eur. Stearic acid 3.00 Ph.Eur. Magnesium stearate 2.00 Ph.Eur. Total core weight 180 mg

The particle size of the extrudate measured by sieve analysis (agomelatine and Soluplus in a mass ratio of 30 : 70)

Particle fraction (mm) Coarse grinding (% by mass fraction) Fine grinding (% mass fraction) Above 1.6 0.2 0 1.4-1.6 1.2 0 1.25-1.4 4.0 0.2 1.0-1.25 17.2 0.2 0.8-1.0 27.2 0.4 0.5-0.8 24.8 0.8 0.25-0.5 16.2 13.2 0.125-0.25 6 40.4

• · · · · 0 9 · · · · · · · ·: .· : i .· ··· ···· · · ·

0.1-0.125 0.6 20.8 Below 0.1 0.8 ....... 23.0

In the coarsely ground extrudate according to Example 7, no admixture of the crystalline form of agomelatine was detected. However, this particle size is not suitable for use in pharmaceutical formulations. The presence of the crystalline form of agomelatine was detected in the finely ground extrudate according to comparative example 7 and in the cores made from this extrudate (see Fig. 9). The dissolution profile of this formulation containing a solid dispersion of agomelatine was significantly slower than the dissolution profile of the reference preparation (see Fig. 10).

Claims (23)

Patent 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-naphthyl)ethyl]acetamide) of the formula I dissolved in a polymeric carrier, wherein the polymeric carrier is copolymer of polyvinylpyrrolidone with polyvinyl acetate in a weight ratio of 3:2, the concentration of agomelatine in the polymer carrier is up to 45% by weight, based on the weight of the solid solution, and a maximum of 60% by weight. solid solution particles are smaller than 0.1 mm. (AND) 2. A thermodynamically stable solid solution of agomelatine according to claim 1, characterized in that the concentration of agomelatine in the solid solution is 15 to 30% by weight. 3. A thermodynamically stable solid solution of agomelatine according to claim 1, characterized in that the mass ratio of agomelatine to the polymer carrier is lower than 1:1.2. 4. A thermodynamically stable solid solution of agomelatine according to claim 3, characterized in that the mass ratio of agomelatine to the polymer carrier is in the range from 1:1.2 to 1:5.7. 5. A thermodynamically stable solid solution of agomelatine according to any one of the preceding claims, characterized in that a maximum of 53% by weight. solid solution particles are smaller than 0.1 mm. 6. A thermodynamically stable solid solution of agomelatine according to any one of the preceding claims, characterized in that at least 20% by weight of particles smaller than 100 micrometers, at least 70 wt.% of particles smaller than 500 micrometers and at least 90 wt.% particles smaller than 1000 micrometers. 7. Method for preparing a thermodynamically stable solid solution of agomelatine according to claims 1 to 6, characterized by the fact that it is prepared by hot melt extrusion technology and subsequent grinding of the resulting extrudate. 8. The method of preparation according to claim 7, characterized in that it is prepared by a process including steps a/ mixing and homogenizing agomelatine with a polymer carrier, which is a copolymer of polyvinylpyrrolidone with polyvinyl acetate in a weight ratio of 3:2, in a weight ratio of agomelatine to the polymer 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/ subsequent cooling of the mixture to a temperature lower than its melting point, during the extrusion process. 9. The preparation method according to claim 8, characterized in that the agomelatine used as starting material is in crystalline form I. 10. The method of preparation according to 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 a polymer carrier. 11. The method of preparation according to claim 10, characterized in that a temperature of 120 °C is used to melt the mixture of agomelatine with a polymer carrier. 12. Pharmaceutical composition for oral use, characterized in that it contains a thermodynamically stable solid solution of agomelatine according to claims 1 to 6, prepared by the method according to claims 7 to 11 and non-hygroscopic pharmaceutically acceptable excipients with a free water content of less than 7% by weight. 13. Pharmaceutical composition according to claim 12, characterized in that the particle size distribution of the agomelatine solid solution is at least 20% by weight. of particles smaller than 100 micrometers, at least 70 wt.% of particles smaller than 500 micrometers and at least 90 wt.% particles smaller than 1000 micrometers. 14. Pharmaceutical composition according to claim 13, characterized in that the excipients are fillers, disintegrants, binders and/or lubricants. 15. Pharmaceutical composition according to claim 14, characterized in that microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, lactose monohydrate, mannitol and/or sorbitol are used as fillers. 16. Pharmaceutical composition according to claim 15, characterized in that microcrystalline cellulose with a water content of up to 1.5% by weight is used as a filler. 17. Pharmaceutical composition according to claim 14, characterized in that crospovidone, low-substituted hydroxypropyl cellulose and/or colloidal silicon dioxide are used as disintegrants. 18. Pharmaceutical composition according to claim 14, characterized in that polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose and/or hydroxyethyl cellulose are used as binders. 19. Pharmaceutical composition according to claim 14, characterized in that magnesium stearate, calcium stearate, stearic acid and/or sodium stearyl fumarate are used as lubricants. 20. Pharmaceutical composition according to claims 12-19, characterized in that it is in the form of tablets. 21. Pharmaceutical composition according to claim 21, characterized in that it is in the form of coated tablets. 22. The method of preparing a pharmaceutical composition according to claims 12 to 21, characterized in that a stable solid solution of agomelatine according to claims 7 to 11 is prepared, to which non-hygroscopic pharmaceutically acceptable excipients with a free water content of less than 7% by weight are further added. while this mixture is processed by dry granulation. 23. A method of preparing a pharmaceutical composition according to claims 12 to 21, characterized in that a stable solid solution of agomelatine according to claims 7 to 11 is prepared, to which non-hygroscopic pharmaceutically acceptable excipients with a free water content of less than 7% by weight are further added. whereby this mixture is processed by direct tableting.