WO2017059877A1

WO2017059877A1 - Pharmaceutical composition containing agomelatine and process for the preparation thereof

Info

Publication number: WO2017059877A1
Application number: PCT/EP2015/001966
Authority: WO
Inventors: Agni GRYPIOTI; Panagiotis BARMPALEXIS
Original assignee: Rontis Hellas S.A.; Pharos Ltd.
Priority date: 2015-10-07
Filing date: 2015-10-07
Publication date: 2017-04-13

Abstract

The present invention relates to a pharmaceutical composition comprising a therapeutically effective quantity of agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, as an active ingredient and a surface stabilizer/ solubility/bio-availability enhancer such as colloidal silicon dioxide, in order to improve the physicochemical stability and enhance the solubility/bioavailability of said active ingredient and a process for the preparation thereof.

Description

PHARMACEUTICAL COMPOSITION CONTAINING AGOMELATINE AND PROCESS

FOR THE PREPARATION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical composition comprising a therapeutically effective quantity of agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, as an active ingredient, and an effective quantity of surface stabilizer/solubility/bio- availability enhancer such as colloidal silicon dioxide capable of enhancing the physicochemical stability of the active ingredient in the finished dosage form and improving the solubility/bioavailability of said active ingredient, and a process for the preparation thereof.

BACKGROUND OF THE INVENTION

Major Depressive Disorder is one of the most common mental disorders. Studies have shown that half of those who have an episode recover and remain well, while the other half will experience chronic recurrence. Recurrence is more likely if symptoms have not been fully resolved with treatment.

Agomelatine is a new first-in-class antidepressant with a novel mode of action at melatonin and serotonin receptors. Agomelatine has an agonistic activity at melatonin receptors and antagonistic actions at certain serotonin receptors within the central nervous system. In addition its activity at recetonin receptors appears to enhance the levels of dopamine and nonadrenaline in the frontal cortex.

Agomelatine is a melatonin receptor agonist and a serotonin 5-HT_2c receptor antagonist used for the treatment of major depressive disorder. Agomelatine' s chemical name is N- [2-(7- methoxynaphthalen-l-yl) ethyl] acetamide and its chemical structure is presented by the following Formula I.

Formula I

Agomelatine is white to almost white crystalline powder that is non-hygroscopic; while it is practically insoluble in water, very slightly soluble in aqueous buffers, and freely soluble in organic solvents such as methanol and dichloromethane. The solubility of the drug in these two solvents is approximately 500 and 80 mg/ml, respectively.

Although, agomelatine is slightly soluble in aqueous solution over the physiological pH range, it can be classified as a drug with high solubility in accordance with the BCS (Biopharmaceutics Classification System) because its dose/solubility ratio is about 100 mL. Nevertheless, based on

CONFIRMATION COPY the renal excretion data it can be concluded that Agomelatine is a highly permeable drug and in combination with its low water solubility is considered as a BCS Class II drug. This poor solubility of agomelatine in aqueous media poses a tremendous challenge to the pharmaceutical formulation scientist as an enhancement in the dissolution rate and bypass of first-pass metabolism during formulation development should be considered in order to have maximum therapeutic efficacy.

Several techniques such as micronization, cyclodextrin complexation, use of surfactants and solubilizers, solid dispersion in water soluble and dispersible carriers, use of salts, prodrugs and polymorphs which exhibit high solubility, micro emulsions and self-emulsifying macro and nano disperse systems have been used to improve the solubility, dissolution rate and bioavailability of poorly soluble drugs.

Moreover, Agomelatine is an active pharmaceutical ingredient that exhibits polymorphism. EP-B- 447 285 discloses a process for the preparation of agomelatine, wherein agomelatine obtained by this process is in crystalline form I. However, crystalline Form I converts into more stable crystalline Form II when subjected to temperatures above 25°C or during formulation processes. Several polymorphs of agomelatine are already known from the literature such as crystalline Form rV disclosed in EP-A- 1752444, Crystalline Form V disclosed in EP-B- 1752443, crystalline Form VI disclosed in EP-A-2058296, and crystalline Form VII disclosed in EP-A- 2690087.

Although, some polymorphs exhibit higher water solubility values than other forms, several physical instability problems arising during storage, such as polymorphic transformation, needs to be considered. In Asian Journal of Pharmaceutical Sciences 8(2013) 181-190 it is described crystalline Form I, II and III of agomelatine, and that the intrinsic dissolution rate of Form I, II and III, is estimated at 76.62, 46.19 and 91.10 μ§/αη²/τϊύη, respectively.

Various known methods have been tested for the industrial preparation of oral dosage forms comprising agomelatine or a pharmaceutically acceptable salt, prodrug or derivative thereof, as an active ingredient due to its useful therapeutical properties. However, the prior art has encountered substantial difficulties in the production of a stable and bioavailable composition of agomelatine.

WO-A-2013/082302 discloses the formation of agomelatine - urea complex in order to improve the stability and shelf-life of the API and improve the dissolution profile or bioavailability of the finished product comprising said agomelatine - urea complex.

WO-A-2012/130837 discloses the use of hydrophilic polymers as surface stabilizer for the preparation of a composition comprising agomelatine in order to improve the stability of the active ingredient. Said composition is prepared by using melt extrusion process.

WO-A-2014/012571 discloses the formation of agomelatine - cyclodextrin complex and a composition comprising said complex.

WO-A-2014/095818 discloses the use of a copolymer of methacrylic acid and divinylbenzene for the preparation of a pharmaceutical composition of agomelatine, wherein agomelatine is present in the composition in stabilized amorphous form.

Although each of the above patents represents an attempt to increase bioavailability and to overcome the stability problems of the active ingredient associated with pharmaceuticals compositions comprising agomelatine, there still exists a need for improving agomelatine's stability and release rate of such pharmaceutical compositions in a less complicated production approach. SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide a pharmaceutical composition for oral administration comprising agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, with enhanced solubility/bioavailability of said active ingredient, which overcomes the deficiencies of the prior art.

Still, it is another object of the present invention to provide a pharmaceutical composition for oral administration comprising agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof as active ingredient, with improved physicochemical characteristics and physicochemical stability of agomelatine.

Moreover, it is another object of the present invention to provide a suitable process for the preparation of a pharmaceutical composition for oral administration comprising a therapeutically effective quantity of agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof as an active ingredient, which is cost effective and reproducible.

In accordance with the above objects of the present invention, a pharmaceutical composition for oral administration is provided comprising a therapeutically effective quantity of agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, as an active ingredient and an effective quantity of colloidal silicon dioxide as a surface stabilizer/ solubility/bio-availability enhancer in order to improve the physicochemical stability of the active ingredient in the finished dosage form and enhance the solubility/bioavailability of said active ingredient.

According to another embodiment of the present invention, a process for the preparation of a pharmaceutical composition for oral administration comprising a therapeutically effective quantity of agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof as an active ingredient, and an effective quantity of colloidal silicon dioxide as a surface stabilizer/ solubility/bio-availability enhancer in order to improve the physicochemical stability of the active ingredient in the finished dosage form and enhance the solubility/bioavailability of said active ingredient, is provided, which comprises: a) dissolving the total quantity of agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, in crystalline Form in aqueous or non-aqueous granulation liquid and suspending/mixing the effective quantity of colloidal silicon dioxide in the resulting solution; b) spray drying the obtained mixture or kneading with suitable excipients such as fillers, binder, disintegrants, glidants and or combination of them by performing wet or fluid bed granulation; c) drying the obtained granules and mixing for appropriate time the obtained granules with extra-granular excipients; d) lubricating the granules of step c) with suitable lubricants; e) compressing the granules resulting from step d) into tablets and optionally f) coating of said tablets.

Further preferred embodiments of the present invention are defined in dependent claims 2 to 6, 8 and 9. Other objects and advantages of the present invention will become apparent to those skilled in art in view of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows XRD pattern of agomelatine compositions of Example 1 according to the present invention with varying concentrations of colloidal silicon dioxide and comparison to XRD agomelatine form I and form II drug crystals

Fig. 2 shows XRD patterns of agomelatine composition 1 according to the present invention on zero time and after one month storage in open vial at accelerated conditions.

Fig. 3 shows XRD patterns of composition 4 and placebo of composition 4 according to the present invention, composition 5 and placebo of composition 5, XRD patterns of agomelatine API crystalline Form I and Form II.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, a pharmaceutical composition comprising agomelatine or salts, prodrug, derivatives thereof is considered to be "stable" if said ingredient degradates less or more slowly than it does on its own and/or in known pharmaceutical compositions and does not transform into other polymorphic forms during storage.

An excipient is considered to be "incompatible" with agomelatine or salts, prodrugs, derivatives thereof if it promotes the degradation of said active ingredient, that is to say, if said active ingredient degrades more or faster in the presence of said excipient when compared with the degradation of said active ingredient on its own. The terms "incompatibility", "compatible" and "compatibility" are defined accordingly.

The active ingredient contained in a dosage form is "bioavailable", if when administered in a dosage form is released from the dosage form, absorbed and reaches, at least the same, concentration levels in plasma as any of the marketed products containing the same quantity of the same active ingredient and intended for the same use.

Although the pharmaceutical composition may be in various forms, the preferred solid forms are tablets, capsules and caplets.

As already mentioned agomelatine or salts, prodrugs, derivatives thereof are susceptible to polymorphism and has a tendency to convert in another polymorphic form when formulated and mixed with excipients or other active substances.

One of the main disadvantages of agomelatine or salts, prodrugs, derivatives thereof is the fact that, it is very labile and consequently many limitations concerning the choice of excipients are raised.

It has been surprisingly found that the object of the present invention is achieved by employing a surface stabilizer/ solubility/bio-availability enhancer, such as colloidal silicon dioxide, in order to improve the physicochemical stability of the active ingredient in the finished dosage form and enhance the solubility/bioavailability of said active ingredient. Colloidal silicon dioxide is a white, fine, amorphous powder. Colloidal silicon dioxide is widely used in pharmaceuticals. Its small particle size and large specific surface area give desirable flow characteristics that are exploited to improve the flow properties of dry powders.

The active ingredient (agomelatine or salts, prodrugs, derivatives thereof) is dissolved in aqueous or non-aqueous granulation liquid and mixed with a suitable amount of colloidal silicon dioxide such as Aerosil™. Subsequently, the above mixture is kneaded with additional excipients by performing wet or fluid bed granulation. After drying the wetted mass and sieving the dried mass, any additional extra-granular excipient is then added. The composition is then mixed until uniform. The resulting mixture may then be compressed into tablets and optionally coated.

Moreover, any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredient of the composition, in order to overcome problems associated with the poor flow properties and unfavorable pharmacotechnical characteristics of these substances, and in order to increase the stability of the drug and the self-life of the pharmaceutical product, and provide a product exhibiting excellent bioavailability.

The composition of the present invention may include further additives (alone or in a combination) such as absorbents, acids, adjuvants, anticaking agents, glidants, antitacking agents, antifoamers, anticoagulants, antimicrobials, antiseptics, diluents, binders, chelating agents, sequestrants, coating agents, colorants, dyes, pigments, complexing agents, softeners, crystal growth regulators, denaturants, desiccants, dehydrating agents, dispersants, solubilizers, emollients, emulsifiers, fillers, flavor masking agents, gelling agents, humectants, lubricants, moisturizers, bufferants, pH control agents, plasticizers, retarding agents, stabilizers, suspending agents, sweeteners, disintegrants, thickening agents, surfactants, opacifiers, coloring agents, preservatives, antigellants, rheology control agents, tonicifiers etc.

Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, isomalt, maltodextrin, maltitol and the like. Diluents may be in the range of 10-90 weight % of the total weight of the composition.

Binders may be selected from acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carbomethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, , sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose, glucose, sorbitol. Binders may be in the range of 1-40 weight % of the total weight of the composition.

Disintegrants may be selected from alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch, low- substituted hydroxypropyl cellulose and the like. Disintegrants may be in the range of 0.1 - 25 weight % of the total weight of the composition.

Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide and the like. Glidants may be in the range of 0.01-2 weight % of the total weight of the composition.

Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, glyceryl behenate and the like. Lubricants may be in the range of 0.01-2 weight % of the total weight of the composition.

Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; aspartame and the like.

Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavor, peppermint flavor and the like.

Solubilizers may be selected from complex forming agents such as cyclodextrins, ion exchange resins, crown ethers and the like.

All percentages stated herein are weight percentages based on total composition weight, unless otherwise stated.

Another embodiment of the present invention is the use of the wet granulation process or fluid bed granulation for the preparation of solid dosage forms for oral administration containing Agomelatine or salt, prodrug, derivative thereof. The steps in the wet granulation technique may be as follows:

a) dissolving the total quantity of agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, in crystalline Form in aqueous or non-aqueous granulation liquid and suspending/mixing a portion of the effective quantity of colloidal silicon dioxide in the resulting solution;

b) spray drying the obtained mixture or kneading with suitable excipients such as fillers, binder, disintegrants, glidants and/or combination thereof by performing wet or fluid bed granulation; c) drying the obtained granules and mixing for appropriate time the obtained granules with extra- granular excipients;

d) lubricating the granules of step c) with suitable lubricants; and

e) compressing the granules resulting from step d) into tablets.

f) optionally, coating the tablets.

The pharmaceutical compositions of the present invention may optionally be prepared by spray drying, wet granulation or fluid bed granulation on a solid carrier such as MCC or sugar spheres, MCC, sugars lactose, maltose, fructose, dextran, glucose; sugar alcohols such as sorbitol, maltitol, polyvinyl alcohol (PVA), low viscosity grades of cellulose derivatives, colloidal silicon dioxide etc. The selection of appropriate materials (excipients, reagents etc.) should be done carefully in order to avoid any incompatibility problems or non-compliance with EMA and FDA guidelines for inactive ingredients.

The tablets may be film coated with functional or non-functional coating.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention:

EXAMPLES

Example 1 : Amorphization of Agomelatine using Colloidal Silicon Dioxide

Several compositions with varying colloidal silicon dioxide concentrations were tested in order to examine agomelatine amorphozation process and physical stability

TABLE 1: Agomelatine compositions with varying silicon dioxide concentrations

Granules of the compositions of Example 1 were prepared according to the following manufacttiring process:

1) Agomelatine was dissolved in granulation liquid

2) The above solution was mixed with the colloidal silicon dioxide

3) The above wetted mixture was granulated with microcrystalline cellulose

4) The obtained granules were dried and sieved from appropriate sieve

The physical nature of the agomelatine active ingredient into the prepared granules has been confirmed through powder X-ray Diffraction (XRD) analysis. As depicted from Fig. 1, the results indicate that in all compositions amorphous agomelatine mixtures with colloidal silicon dioxide were prepared.

Further, as shown in Fig. 2, wherein the XRD patterns of composition 1 of Example 1 at zero time and after 1 month storage in open vial at accelerated conditions (ACC: 40°C - 75%RH) is presented, the X-RD analysis shows that no polymorphic transformation was observed during storage, indicating good physical stability. Example 2: Preparation of Agomelatine 25mg Film Coated Tablets

In order to evaluate the effect of colloidal silicon dioxide as surface stabilizer/solubility/bio- availability enhancer on agomelatine amorphization process, two different compositions were prepared: 1) composition 4, wherein the amorphous mixture of agomelatine active ingredient with colloidal silicon dioxide was used and 2) composition 5, wherein crystalline agomelatine (form I) was used.

A preferred Agomelatine composition 4 according to the present invention is illustrated in Table 2 below, while Table 3 shows quantitative and qualitative Agomelatine composition 5.

TABLE 2: Quantitative and qualitative Agomelatine composition 4 according to the present invention

Tablets of agomelatine composition 4 according to the present invention were prepared according to the following manufacturing process:

A. Dissolve agomelatine active ingredient in crystalline Form I in granulation liquid and suspend/mix colloidal silicon dioxide in the resulting solution.

B. Granulate/Knead the suspension/mixture of step A with Microcrystalline cellulose. Pass the wet mass through cone mill.

C. Dry the above granules to appropriate LOD.

D. Pass the dried granules through appropriate sieve.

E. Mix for appropriate time the granules from step D with extra-granular excipients.

F. Lubricate powder from step E with magnesium stearate. G. Compress the powder resulting from step F into tablets.

H. Optionally, coat the tablets from step G with Opadry 200-F©.

TABLE 3: Agomelatine composition 5

Tablets of composition 5 were prepared according to the following manufacturing process:

A) . Dissolve Hydroxyethyl-Cellulose in granulation liquid and suspend/mix agomelatine active ingredient in crystalline form I in the resulting solution.

B) . Granulate/Knead the suspension/mixture of step A with Microcrystalline cellulose, Lactose and Croscarmellose Sodium. Pass the wet mass through cone mill; C). Dry the above granules to appropriate LOD (loss of Drying); D). Pass the dried granules through appropriate sieve; E). Mix for appropriate time the granules from step D with extra-granular excipients; F). Lubricate powder from step E with magnesium stearate; G). Compress the powder resulting from step F into tablets; and H). Optionally, coat the tablets from step G with Opadry 200-F©.

Analytical procedures and tests were performed for Agomelatine film-coated tablets, including tests for physical appearance, identification, average mass and mass uniformity, uniformity of dosage units, loss on drying, hardness, assay, related substances, thickness, disintegration times, dissolution rates and microbiological limit tests, in order to prove that tablets of the invention meet the current technical specifications.

The crystallographic characteristics of the prepared tablets from composition 4 and composition 5 are shown in Figure 3, namely XRD pattern of Composition 4, XRD pattern of Placebo of Composition 4, XRD pattern of Composition 5, XRD pattern of Placebo of Composition 5, and XRD pattern of Agomelatine API in crystalline Form I, and Form II, respectively.

As depicted form Figure 3, the active ingredient agomelatine of the tablet of composition 4 is completely amorphous, while in the tablet of composition 5 the active ingredient agomelatine is in crystalline form I. Hence, colloidal silicone dioxide is able to prepare stable amorphous agomelatine Film Coated tablets.

One of the most critical pharmacotechnical tests is the dissolution test as it is strongly correlated with the bioavailability of the product. For the dissolution method a USP apparatus II (rotating paddle method) Agilent VK 708DS Paddles was run at 75rpm, 37°C ± 0.5 °C, for 60min, while as dissolution medium 900 ml of 0.1N HC1 was used. Sink conditions were maintained throughout the test. An aliquot of 4 ml of samples was collected at 5, 10, 15, 20, 30, 45 and 60 min using an automatic sampler and assayed for agomelatine content by HPLC.

Dissolution rate results for each composition tested are given in Table 4.

TABLE 4: Dissolution profiles of Agomelatine composition 4 and composition 5

The results show that composition 5 is not completely dissolved in about 60 minutes.

Further, from table 4, it is shown that the use of colloidal silicon dioxide for the amorphization of agomelatine composition 4 leads to an increase in dissolution rate in comparison to composition 5 wherein the tablet contains agomelatine in crystal form.

It is a generally known problem for pharmaceutical compositions of low solubility active ingredients that even though dissolution test provides satisfactory results, many times in vivo results depart from what it is expected. For this kind of drugs with low solubility and high first pass metabolism the dissolution test is not so discriminative, thus only the pharmacokinetic study results are representative regarding the formulations. Example 3: In- Vivo comparison of Agomelatine 25 mg FC tablets

According to the present invention the bioavailability and pharmacokinetic profile was determined in an "in vivo" single-dose study in order to evaluate the effect of the dissolution enhancement when colloidal silicon dioxide is used for the amorphization of agomelatine. Two trials were tested:

(A) TRIAL 1, where colloidal silicon dioxide is used for the amorphozation of agomelatine having a similar dissolution profile to composition 4, and

(B) TRIAL 2, where agomelatine in the tablet is in crystal form having a similar dissolution profile to composition 5.

A randomized, open label, balanced, two treatment, two period, two sequence, single dose, crossover, in vivo study in healthy adult human subjects under fasting conditions was used. Treatments were allocated to subjects as indicated by a randomization schedule generated using statistical techniques. Blood samples were drawn before dosing and up to 12.00 hours after dosing. The Plasma concentrations of agomelatine was analyzed using a validated analytical method. 12 healthy, adult, human subjects were enrolled in the study.

Table 5 summarizes the Cmax and AUCo-t values for both tested trials. Results indicate that in the case of TRIAL 1, wherein colloidal silicon dioxide is used for the amorphization of agomelatine, the Cmax and AUCo-t values of agomelatine API are increased compared to TRIAL 2, where colloidal silicon dioxide is not used and agomelatine in the tablet is in crystal form.

TABLE 5: Pharmacokinetic analysis of TRIAL 1 and TRIAL 2

wherein:

C max=(peak concentration) is the highest concentration reached by the drug in plasma after dosing;

AUCo-t =(aiea under the curve) is the area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, as calculated by the linear trapezoidal method.

These data show that TRIAL 1 of the present invention can therefore be considered, with respect the pharmacological performance, the best bioavailable formulation with respect to TRIAL 2.

The increased bioavailability of TRIAL 1 can be attributed to the formation of a fine dispersion between colloidal silica dioxide and Agomelatine. The very large surface of colloidal silicon dioxide, on which the active ingredient is absorbed, results to an increase of the specific surface area and contribute to the excess of bioavailability.

Moreover, the good results regarding the physicochemical characteristics, the excellent stability of the drug product, as well as the particular manufacturing process followed, indicate the advantages of the present invention relatively to the commonly used methods and excipients used for the formulation of agomelatine.

The agomelatine active ingredient, as starting material used in all compositions of the present invention was in crystalline Form I. During the stability studies of Agomelatine film-coated tablets according to the present invention and under storage conditions, the solid state of Agomelatine remained in amorphous form, when colloidal silicon dioxide was used. In order to corifirm that statement, powder XRD has been performed. Diffractograms of agomelatine 25 mg film-coated tablets, placebo and agomelatine active ingredient were compared confirming the presence of the drug substance in its amorphous state and its physical stability in the finished dosage form (Fig. 2 and 3).

Hence, the above given examples shows that colloidal silicon dioxide is able to act as a surface stabilizer/solubiUty/bio-availability enhancer in order to improve the physicochemical stability of the active ingredient in the finished dosage form by protecting said active ingredient from polymorphous conversion, and improve the solubility and in- vivo bioavailability of said active ingredient

While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

1. A pharmaceutical composition for oral admimstration comprising a therapeutically effective quantity of agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, as an active ingredient and an effective quantity of colloidal silicon dioxide as a surface stabilizer/ solubility/bio-availability enhancer, in order to improve the physicochemical stability of the active ingredient in the finished dosage form and enhance the solubility/bioavailability of said active ingredient.

2. The pharmaceutical composition according to claim 1, wherein said active ingredient agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, as starting material, is in crystalline form.

3. The pharmaceutical composition according to claim 2, wherein agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, in the finished dosage form is in amorphous form and said colloidal silicon dioxide as a surface stabilizer/solubility/bio-availability enhancer inhibits the recrystallization of said amorphous agomelatine.

4. The pharmaceutical composition according to claim 1, wherein the amount of agomelatine in said composition is in the range of 1-50 weight % of the total weight of the composition.

5. The pharmaceutical composition according to claim 1, wherein the amount of colloidal silicon dioxide in the composition is at least 1 weight % of the total weight of the composition.

6. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition further comprises pharmaceutically acceptable additives selected from a group comprising of absorbents, acids, adjuvants, anticaking agents, glidants, antitacking agents, antifoamers, anticoagulants, antimicrobials, antiseptics, diluents, binders, chelating agents, sequestrants, coating agents, colorants, dyes, pigments, complexing agents, softeners, crystal growth regulators, denaturants, desiccants, dehydrating agents, dispersants, solubilizers, emollients, emulsifiers, fillers, flavor masking agents, gelling agents, humectants, lubricants, moisturizers, bufferants, pH control agents, plasticizers, retarding agents, stabilizers, suspending agents, sweeteners, disintegrants, thickening agents, surfactants, opacifiers, coloring agents, preservatives, antigellants, rheology control agents, tonicifiers and their combinations thereof.

7. A process for the preparation of a pharmaceutical composition for oral admimstration comprising a therapeutically effective quantity of agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, as active ingredient and an effective quantity of colloidal silicon dioxide as a surface stabilizer/ solubility/bio-availability enhancer in order to improve the physicochemical stability of the active ingredient in the finished dosage form and enhance the solubility/bioavailability of said active ingredient, which comprises:

a) dissolving the total quantity of agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, in crystalline Form in aqueous or non-aqueous granulation liquid and suspending/mixing the effective quantity of colloidal silicon dioxide in the resulting solution; b) spray drying the obtained mixture or kneading with suitable excipients such as fillers, binder, disintegrants, glidants and/or combination thereof by performing wet or fluid bed granulation; c) drying the obtained granules and mixing for appropriate time the obtained granules with extra- granular excipients;

d) lubricating the granules of step c) with suitable lubricants; and

e) compressing the granules resulting from step d) into tablets.

8. The process for the preparation of a pharmaceutical composition according to claim 8, wherein further comprises coating the tablets.

9. The process for the preparation of a pharmaceutical composition according to claim 8, wherein the agomelatine or a pharmaceutically acceptable salt, prodrug, or derivative thereof, in the prepared tablets is in amorphous form and said colloidal silicon dioxide as a surface stabilizer/ solubility/bio-availability enhancer inhibits the recrystallization of said amorphous agomelatine.