WO2013120463A1

WO2013120463A1 - A method for the manufacture of a polymorphously stable pharmaceutical composition containing agomelatine

Info

Publication number: WO2013120463A1
Application number: PCT/CZ2013/000012
Authority: WO
Inventors: Jaroslav Rezac; Anna Hanovska; Daniel PRIBYL; Ondrej Dammer; Alena Prokopova
Original assignee: Zentiva, K.S.
Priority date: 2012-02-15
Filing date: 2013-02-11
Publication date: 2013-08-22
Also published as: CZ2012108A3

Abstract

The invention provides a thermodynamically stable solid solution of agomelatine, containing agomelatine dissolved in a polymeric carrier, which is polyvinylpyrrolidone and/or its copolymer, a method for the manufacture thereof and pharmaceutical compositions containing agomelatine (N-[2-(7-methoxy-1-naphtyl)ethyl]acetamide) of formula (I) and a method of their preparation.

Description

A METHOD FOR THE MANUFACTURE OF A POLYMORPHOUSLY STABLE PHARMACEUTICAL COMPOSITION CONTAINING AGOMELATINE

Technical Field

The invention relates to pharmaceutical compositions containing agomelatine (N-[2-(7- methoxy-l -naphtyl)ethyl]acetamide) of formula (I) and a method of their preparation.

(I)

Background Art

Formulations containing agomelatine belong to the group of antidepressant drugs. Agomelatine is a melatonergic agonist (of MTi and ΜΤ₂ receptors) and an antagonist of serotonergic 5 -HT₂c receptors .

Agomelatine was first mentioned in the EP patent 0 447 285 (Adir et Compagnie). There are a number of polymorphous 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 WO2007015002 (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 WO201 1006387 (Zhejiang Huahai Pharmaceutical Co., Ltd.) describes forms A, B, and C of agomelatine.

Out of these polymorphous forms it is form II that is the most stable. During production and storage of formulations containing agomelatine of another polymorphous form than form II the other form or forms generally get transformed into the thermodynamically more stable form II sooner or later.

Agomelatine is available in the market in two products (Valdoxan and Thymanax, both with the content of 25 mg) of the company Servier. Both these products contain agomelatine in the polymorphous form II.

Pharmacokinetic studies have shown that the biological availability of agomelatine is very low when administered orally compared to parenteral administration and is strongly variable when agomelatine is administered to different patients (interindividual variability) or even repeatedly to the same patient (intraindividual variability). Problems with the biological availability and variability of pharmaceutical compositions of agomelatine with instantaneous release motivated the search for such formulations that would overcome these problems.

The present invention provides biologically available pharmaceutical compositions in the form of solid solutions of agomelatine, which provide uniform releasing of agomelatine, ensure a suitable dissolution profile and prevent undesired re-crystallization of agomelatine in the composition.

Disclosure of Invention

The invention consists essentially in a thermodynamically stable solution of agomelatine containing agomelatine dissolved in a polymeric carrier and a pharmaceutical composition containing a stable solid solution of agomelatine and non-hygroscopic pharmaceutically acceptable auxiliary substances with a low water content. The polymeric carrier used is polyvinylpyrrolidone and/or its copolymers. The resulting formulations appear to be thermodynamically stable, which was confirmed by stability testing under different conditions (of natural and accelerated stability). In addition, the rate of releasing of the active substance (dissolution) can be controlled in these formulations. It has been found out that the releasing rate of the active substance depends on the polymer type, size of extrudate particles and concentration of the active substance in the polymer.

Detailed description of the invention

An aspect of the invention provides thermodynamically stable solid solutions of agomelatine that contain agomelatine dissolved in a polymeric carrier, which is polyvinylpyrrolidone and/or its copolymers.

The polymeric carrier for the solution according to the invention is meant to include polyvinylpyrrolidone and/or its copolymers.

A solid solution of agomelatine and such a polymeric carrier is thermodynamically stable and no undesired re-crystallization of agomelatine occurs in it. Compositions containing a solid solution of agomelatine and a polymeric carrier according to the presented invention exhibit faster and better solubility than the reference formulation of agomelatine.

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

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

The ratio of agomelatine to the polymeric 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).

Polyvinylpyrrolidone (PVP) and/or its copolymers can be used as the polymeric carrier in the formulation according to the invention. Polymers with a lower molecular weight in the range of approximately 2,000 to 70,000 are convenient, especially polyvinylpyrrolidone with the molecular weight of 2,000 - 34,000 (e.g. Kollidon 12 PF, Kollidon 17 PF, Kollidon 25), or copolymers of polyvinylpyrrolidone with the molecular weight of 45,000 - 70,000. The copolymer of polyvinylpyrrolidone with polyvinylacetate (copovidone) is especially convenient, mainly in the weight ratio of 3 :2 (Kollidon VA64).

Another aspect of the presented 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 and are non- hygroscopic.

Microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, lactose monohydrate, mannitol and/or sorbitol can be used as a filler. Microcrystalline cellulose is the preferred filler, especially microcrystalline cellulose with the maximum water content of 1.5% by weight (e.g. of the Avicel PHI 12 type).

Crosspovidone, low-substituted hydroxypropyl cellulose and/or colloidal silicon dioxide can be used as a disintegrant. Out of these, crosspovidone and silicon dioxide are preferred, a combination of these two disintegrants being especially preferred.

Povidone, copovidone, hydroxypropyl cellulose and/or hydroxyethyl cellulose can be used as the binder.

Magnesium stearate, calcium stearate, stearic acid and/or sodium stearyl fumarate can be used as a lubricant. A preferred solution includes use of a combination of magnesium stearate and stearic acid.

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

This involves heating of a pre-homogenized mixture of agomelatine and the polymer and optionally other auxiliary substances to a suitable temperature, at which agomelatine can be dissolved in the melted polymer. In a preferred embodiment agomelatine of crystalline form I is used as the starting material. 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 API in the polymer. For the preferred copolymer of polyvinylpyrrolidone with polyvinylacetate, preferably in the weight ratio of 3:2 (Kollidon VA64) an optimum temperature has proved to be 120°C to 140°C. This was confirmed by an XRPD analysis that proved absence of any crystalline form. At lower temperatures, e.g. 95°C or 1 10°C, a solid dispersion of agomelatine was obtained, not a solid solution.

During the extrusion process after dissolution of 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 using a rotating cutter or another method into small pieces and is ready for further processing.

The production of extrudate has been verified in two types of extruders (Thermofisher, ThreeTec). The amount of produced extrudate per hour is up to 1 kg/hour as confirmed by tests and the extruder torque was 35-125 N.m.

A preferred distribution of particle sizes of ground extrudate is at least 20% by weight of particles smaller than 100 micrometres, at least 70% by weight of particles smaller than 500 micrometers and at least 90% by weight of particles smaller than 1000 micrometres.

The obtained solid solution can be further used for the manufacture of a pharmaceutical composition.

For the preparation of a pharmaceutical composition containing a solid solution of agomelatine technologies omitting the use of a solvent (e.g. water or ethanol) were used with regard to the characteristics of the active substance. These are the direct tabletting or dry . granulation technologies.

Direct tabletting represents a technological process wherein the auxiliary substances are gradually, in several steps , sieved and mixed with an extrudate containing agomelatine in such a way that this results in a sufficiently homogeneous mixture of substances for tabletting. 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, can be an alternative technology. Compaction means a manufacturing method, in which an extrudate containing agomelatine and other excipients are homogenized in one or several production steps, followed by compression, by application of pressure in a compactor, to produce a band of compact material, which is subsequently ground in a sieving device to a defined size of particles resulting from the mesh size. The obtained granulate is either used directly for the production of tablets or one or more excipients are admixed to it and it is then used for the production of cores or tablets. The cores are coated with a suspension consisting of common excipients.

The next production stage is tabletting and then coating and adjustment of tablets.

The use of Kollidon VA64 results in the production of a stable form of both an extrudate with a larger size of particles, as well as an extrudate after grinding into a fine particle size, and of the final dosage form (coated tablets) after the production and during storage of packed tablets for 1 month at 40°C and 75% relative humidity. From the point of view of XPRD analysis this is confirmed by absence of any crystalline form in the sample.

On the other hand, when a copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol (Soluplus) was used, crystalline form II of agomelatine was partly detected in the extrudate, and crystalline form II was partly detected in the final dosage form (coated tablets) after the production as well - see the comparative Example 3.

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

Brief Description of Drawings

Fig. 1: XRPD analysis - confirmation of absence of any crystalline form of agomelatine in the extrudate of Example 1 (1 - coarsely ground extrudate, 2 - finely ground extrudate, 3

- the polymer Kollidon VA64 alone, 4 - control: agomelatine of crystalline form I)

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

Fig. 3: XRPD analysis - confirmation of absence of any crystalline form of agomelatine in the extrudate of Example 2 (1 - coarsely ground extrudate, 2 - finely ground extrudate, 3

- control: agomelatine of crystalline form II)

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

Fig. 5 : XRPD analysis - demonstration of presence of a mixture of crystalline form II in the finely ground extrudate of Example 3 (1 - finely ground extrudate, 2 - control: agomelatine of crystalline form II)

Fig. 6: Dissolution profile - Examples 1, 2, 3 and the reference (original) formulation

1 - Example 1 (batch 23061 1), 2 - Example 2 (batch 20051 1), 3 - Example 3 (batch 21051 1), 4

- reference formulation

(batch 20051 1 - Example 2 and batch 23061 1 - Example 1 even more exhibit faster dissolution profiles as compared to the reference formulation; conversely, batch 21051 1 - Example 3 shows considerable deceleration of the dissolution profile as compared to the reference formulation) Examples

EXAMPLE 1

Agomelatine and Kollidon VA64 in a weight ratio of 15 : 85 are sieved through a 1.0mm sieve and then homogenized for 10 mins in a stainless steel container. The obtained mixture is poured into the hopper of the POLYLAB OS Thermofisher hot melt extruder. The mixture is continuously fed to a screw conveyor, wherein it gradually passes from the filling section through heated sections, wherein the polymer is blended, compressed and melted. The process temperature is 135°C. At the end of the screw conveyor the melted mixture is pushed through openings (matrices) out of the extruder. After air cooling and solidification of the extrudate it is ground with the use of rotating cutters. The produced coarsely ground extrudate is further divided in another grinder down to a defined particle size, see Example 1 - fine grinding. The finely ground extrudate is used for the next production stage, wherein the auxiliary substances are gradually, in several steps, sieved (through a 1.0mm sieve) and mixed with the extrudate containing agomelatine in order to obtain a sufficiently homogeneous mixture of substances for tabletting. The cores are coated with a suspension consisting of common excipients.

Product composition - cores

Amount/core Specifications

Substance (mg)

Extrudate 166.67

Agomelatine (15%) - 25.00 In-house

- Kollidon VA64 (85%) - 141.67 Ph.Eur.

Microcrystalline cellulose 109.94 Ph.Eur.

Colloidal silicon dioxide 2.00 Ph.Eur.

Crosspovidone 66.38 Ph.Eur.

Stearic acid 3.00 Ph.Eur.

Magnesium stearate 2.00 Ph.Eur.

Total core weight 350 mg — f extrudate particles (agomelatine and Kollidon VA64 in a weight ratio of 15 : 85)

Particle fraction (mm) Coarse grinding Fine grinding

Over 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

Under 0.1 0 47.6 No crystalline form of agomelatine was detected in the ground extrudate from Example 1 or in the cores made of this extrudate (see Figs. 1 and 2). The dissolution profile was faster than that of the reference formulation (see Fig. 6).

EXAMPLE 2

The process is the same as in Example 1. It is only the composition that is different - Agomelatine and Kollidon VA64 in a weight ratio of 30 : 70 - see Example 2. The process temperature is 120°C.

Product composition - cores

Size of extrudate particles (agomelatine and Kollidon VA64 in a weight ratio of 30 : 70)

No crystalline form of agomelatine was found in the ground extrudate from Example 2 or in the cores made of this extrudate (see Figs. 3 and 4). The dissolution profile was faster than that of the reference formulation (see Fig. 6). EXAMPLE 3 - COMPARATIVE

Agomelatine and Soluplus in a weight ratio of 30 : 70 are sieved through a 1.0mm sieve and then homogenized for 10 mins in a stainless steel container. The obtained mixture is poured into the hopper of the POLYLAB OS Thermofisher hot melt extruder. The mixture is continuously fed to a screw conveyor, wherein it gradually passes from the filling section through heated sections, wherein the polymer is blended, compressed and melted. The process temperature is 120°C.

At the end of the screw conveyor the melted mixture is pushed through openings (matrices) out of the extruder. After air cooling and solidification of the extrudate it is ground with the use of rotating cutters. The produced coarsely ground extrudate is further divided in another grinder down to a defined particle size, see Example 1 - fine grinding. The finely ground extrudate is used for the next production stage, wherein the auxiliary substances are gradually, in several steps, sieved (through a 1.0mm sieve) and mixed with the extrudate containing agomelatine in order to obtain a sufficiently homogeneous mixture of substances for tabletting. The cores are coated with a suspension consisting of common excipients, see Example 1.

Product com osition - cores

f extrudate particles (agomelatine and Soluplus in a weight ratio of 30 : 70)

Coarse grinding Fine grinding

Particle fraction (mm)

(weight % of fraction) (weight % of fraction)

Over 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

0.1 - 0.125 0.6 20.8

Under 0.1 0.8 23.0 Presence of a crystalline form of agomelatine was detected in the ground extrudate from_, the comparative Example 3, as well ^' as in the cores made of this extrudate (see Fig. 5). The dissolution profile of this formulation was considerably slower than that of the reference, formulation (see Fig. 6).

Claims

1. A thermodynamically stable solid solution of agomelatine, characterized in that it contains agomelatine (N-[2-(7-methoxy-l -naphtyl)ethyl]acetamide) of formula I, dissolved in a polymeric carrier, which is polyvinylpyrrolidone and/or its copolymer.

(I)

2. The thermodynamically stable solid solution of agomelatine according to claim 1 , characterized in that it contains agomelatine dissolved in a polymeric carrier, which is a copolymer of polyvinylpyrrolidone.

3. The thermodynamically stable solid solution of agomelatine according to claim 1 , characterized in that the concentration of agomelatine in the solid solution is up to 45% by weight.

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

5. The thermodynamically stable solid solution of agomelatine according to claim 1 , characterized in that the weight ratio of agomelatine to the polymeric carrier is lower than 1 : 1.2.

6. The thermodynamically stable solid solution of agomelatine according to claim 5, characterized in that the weight ratio of agomelatine to the polymeric carrier is in the range of from 1 : 1.2 to 1 : 5.7.

7. The thermodynamically stable solid solution- of agomelatine according to any one of the previous claims, characterized in that the polymeric carrier used is polyvinylpyrrolidone and/or its copolymers with a molecular weight of 2,000 - 70,000.

8. The thermodynamically stable solid solution of agomelatine according to claim 7, characterized in that the polymeric carrier used is polyvinylpyrrolidone with a molecular weight of 2,000 - 34,000.

9. The thermodynamically stable solid solution of agomelatine according to any one of claims 1 -7, characterized in that the polymeric carrier used is a copolymer of polyvinylpyrrolidone with a molecular weight of 2,000 - 70,000.

10. The thermodynamically stable solid solution of agomelatine according to claim 9, characterized in that the polymeric carrier used is a copolymer of polyvinylpyrrolidone with polyvinylacetate with a molecular weight of 45,000 - 70,000.

1 1. The thermodynamically stable solid solution of agomelatine according to claim 10, characterized in that the units of the copolymer of polyvinylpyrrolidone with polyvinylacetate are in a weight ratio of 3 :2.

12. A method for the preparation of a thermodynamically stable solid solution of agomelatine according to any one of claims 1 to 1 1 , characterized in that it is prepared using the hot melt extrusion technology.

13. The method according to claim 12, characterized in that the process includes the following steps

a/ mixing and homogenizing agomelatine with a polymeric carrier 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 that is sufficient to melt the mixture and

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

14. The method according to claim 12, characterized in that agomelatine used as the starting material is in crystalline form I.

15. The method according to claim 13, characterized in that a temperature in the range of 100 - 140°C is used to melt the mixture of agomelatine with the polymeric carrier.

16. A pharmaceutical composition for oral administration, characterized in that it contains a solid solution of agomelatine according to any one of claims 1 -15 and non-hydroscopic pharmaceutically acceptable auxiliary substances with a free water content lower than 1.5% by weight.

17. The pharmaceutical composition according to claim 16, characterized in that the distribution of particle sizes of the solid solution of agomelatine is at least 20% by weight of particles smaller than 100 micrometres, at least 70% by weight of particles smaller than 500 micrometres and at least 90% by weight of particles smaller than 1000 micrometres.

18. The pharmaceutical composition according to claim 16, characterized in that the auxiliary substances are fillers, disintegrants, binders and/or lubricants.

19. The pharmaceutical composition according to claim 18, characterized in that microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, lactose monohydrate, mannitol and/or sorbitol is used as the filler .

20. The pharmaceutical composition according to claim 19, characterized in that microcrystalline cellulose with a water content of up to 1.5% by weight is used as the filler.

21. The pharmaceutical composition according to claim 18, characterized in that crosspovidone, low-substituted hydroxypropyl cellulose and/or colloidal silicon dioxide is used as the disintegrant.

22. The pharmaceutical composition according to claim 18, characterized in that polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose and/or hydroxyethyl cellulose is used as the binder.

23. The pharmaceutical composition according to claim 18, characterized in that magnesium stearate, calcium stearate, stearic acid and/or sodium stearyl fumarate is used as the lubricant.

24. The pharmaceutical composition according to any one of claims 16-23, characterized in that it is in the form of tablets.

25. A method for the preparation of the pharmaceutical composition according to any one of claims 16-24, characterized in that a stable solid solution of agomelatine is prepared according to any one of claims 12 to 15, to which non-hygroscopic pharmaceutically acceptable auxiliary substances with a free water content lower than 1.5% by weight are further added, this mixture being processed by dry granulation.

26. A method for the preparation of the pharmaceutical composition according to any one of claims 16-24, characterized in that a stable solid solution of agomelatine is prepared according to any one of claims 12 to 15, to which non-hygroscopic pharmaceutically acceptable auxiliary substances with a free water content lower than 1.5% by weight are further added, this mixture being processed by direct tabletting.