EP4687849A1

EP4687849A1 - Stable pharmaceutical composition containing selexipag and process for the preparation thereof

Info

Publication number: EP4687849A1
Application number: EP24718703.2A
Authority: EP
Inventors: Agni GRYPIOTI; George Papandreou
Original assignee: Pharos Ltd; Rontis Hellas SA
Current assignee: Pharos Ltd; Rontis Hellas SA
Priority date: 2024-03-13
Filing date: 2024-03-13
Publication date: 2026-02-11
Also published as: WO2025190465A1

Abstract

The present invention relates to a stable pharmaceutical composition comprising a therapeutically effective quantity of selexipag or a pharmaceutically acceptable salt or derivative thereof, as an active ingredient and a polymer, as a suspending agent and a process for the preparation thereof.

Description

STABLE PHARMACEUTICAL COMPOSITION CONTAINING SELEXIPAG AND PROCESS FOR THE PREPARATION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical composition for oral administration, and in particular to a composition comprising a solid dispersion of a therapeutically effective quantity of selexipag or a pharmaceutically acceptable salt or derivative thereof, as an active ingredient, and a polymer as suspension agent in order to improve the stability, dissolution and bioavailability of said active ingredient. Furthermore, the present invention relates to a process for the preparation of said pharmaceutical composition.

BACKGROUND OF THE INVENTION

Pulmonary hypertension (PH) has been classified by the World Health Organization (WHO into five groups: Group 1 : pulmonary arterial hypertension (PAH); Group 2: PH with left heart disease; Group 3: PH with lung disease and/or hypoxemia; Group 4: PH due to chronic thrombotic and/or embolic disease; and Group 5: miscellaneous conditions (e.g. sarcoidosis, lymphangiomatosis and compression of pulmonary vessels).

Pulmonary arterial hypertension (PAH) is a serious, complex and life-threatening disease of the pulmonary vasculature, characterized by profound vasoconstriction and an abnormal proliferation of smooth muscle cells in the walls of the pulmonary arteries. Severe stenosis of the blood vessels in the lungs leads to very high pulmonary arterial pressure. These high pressure in the blood vessels makes it difficult to carry blood to the lungs. Patients with PAH suffer from extreme shortness of breath as the heart struggles to pump against the high pressure.

Various methods of treating PAH focus on reducing symptoms, disease progression and hospitalization and enhancing quality of life. Such therapeutic methods include administration of vasodilators, endothelin receptor antagonists, calcium channel blockers, anticoagulants, supplemental oxygen therapy and diuretics.

Selexipag is a prostacyclin receptor agonist that causes vasodilation of the blood vessels in the lungs so as to allow blood to flow easily and is used in the therapy of pulmonary arterial hypertension (PAH).

Selexipag is chemically known as 2-{4-[(5,6- diphenylpyrazin-2-yl) (isopropyl)amino]butoxy} - N-(methylsulfonyl)acetamide and is a pale yellow crystalline powder that is practically insoluble in water.

Selexipag is commercially available under the brand name Uptravi™ (a film-coated tablet for oral administration). Each film-coated tablet of Uptravi™ contains 200, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg of Selexipag and the following inactive ingredients: mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, and magnesium stearate. In addition, the film coating contains hypromellose, propylene glycol, titanium dioxide, carnauba wax along with iron oxide red, iron oxide yellow, iron oxide black or mixtures thereof.

Various methods are already known for the industrial preparation of dosage forms comprising Selexipag, due to their useful therapeutic properties. However, the prior art has encountered substantial difficulties in the production of a stable composition of a desirable dissolution and bioavailability because of the low water solubility issues of said active ingredient. Although in the prior art there are various methods to provide an improved stable composition of Selexipag there still exists the need for a pharmaceutical composition which overcomes the related stability and dissolution problems, and bioavailability of said active ingredient.

SUMMARY OF THE INVENTION

It is therefore, an object of the present invention to provide a stable solid pharmaceutical composition for oral administration comprising a solid dispersion of selexipag or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, and a polymer as a suspension agent, which is stable and bioavailable, with sufficient shelf-life and good pharmacotechnical properties.

Moreover, it is another object of the present invention to provide a suitable process for the preparation of a stable immediate release composition for oral administration comprising a solid dispersion comprising a therapeutically effective quantity of selexipag or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, and a binder polymer agent as a suspension agent, which is cost effective and reproducible and overcomes the difficulties encountered in the production of said dosage form due to low water solubility issues of selexipag.

In accordance with the above objects of the present invention, a stable pharmaceutical composition for oral administration is provided comprising a solid dispersion comprising a therapeutically effective quantity of selexipag or a pharmaceutically acceptable salt, or derivative thereof, as an active ingredient and a binder polymer as a suspension agent in order to improve stability, dissolution and bioavailability of said active ingredient in the finished dosage form.

According to another embodiment of the present invention, a process for the preparation of a pharmaceutical dosage form for oral administration comprising a solid dispersion of a therapeutically effective quantity of selexipag or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, and a binder polymer as a suspension agent in order to improve stability, dissolution and bioavailability of said active ingredient in the finished dosage form, is provided, wherein said process comprises the following steps:

Step 1 : Dispensing and sieving of the active ingredient and intra-granular excipients: Weigh individually the active pharmaceutical ingredient (API) selexipag, mannitol, as a first diluent, a portion of the total quantity of maize starch as a second diluent, a portion of the total quantity of Low-Substituted Hydroxypropyl Cellulose, as a disintegrant and the total quantity of Hydroxypropyl Cellulose as a binder polymer agent, and sieve through appropriate sieve;

Step 2: Preparation of API suspension for wet granulation: in a suitable mixing vessel dissolve a portion of the total quantity of binder polymer Hydroxypropyl Cellulose in water until a clear solution is obtained and add weighted active ingredient and mix until a homogeneous suspension is obtained;

Step 3: Wet granulation: in a high shear mixer granulator add individually the remaining intra- granular excipients of step 1, pre-mix them for suitable time, add in said high shear mixer granulator the active ingredient suspension obtained from step 2, as a granulation liquid and granulate until a homogenized wet mixture is obtained;

Step 4: Drying: the granules obtained from step 3 are dried in fluid bed dryer to appropriate loss on drying (LOD);

Step 5: Sizing: Pass the granules obtained from step 4 to an appropriate sieve; Step 6: Dispensing and sieving of extra-granular excipients: Weigh individually the remaining quantity of Maize starch as a second diluent and the remaining quantity of Low-Substituted Hydroxypropyl Cellulose as a disintegrant and sieve through appropriate sieve;

Step 7: Mixing: In a suitable blender add the granules obtained from step 5 and the extra-granular excipients from step 6 and mix for appropriate time;

Step 8: Lubrication: Weigh individually magnesium stearate, as a lubricant, sieve it through appropriate sieve and mix with the blend obtained from step 7 into a blender for appropriate time, and

Step 9: Compression: Compress the homogeneous powder obtained from step 8 under controlled humidity in tablets on a rotary tabletting machine using appropriate punches.

Further preferred embodiments of the present invention are defined in dependent claims 2 to 10, and 12.

Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, a pharmaceutical composition comprising selexipag or salts or derivatives thereof is considered to be “stable” if said active ingredient degradates less or more slowly than it does on its own and/or in known pharmaceutical compositions during storage.

An excipient is considered to be “incompatible” with selexipag or salts, or derivatives thereof if it promotes the degradation of said active ingredient, that is to say, if said active ingredient degradates 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.

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

For the purposes of the present invention, a "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance, the continuous phase. In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In the present case, a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase).

For example, a solid dispersion is a co-precipitate of Selexipag with at least one polymer. A "Coprecipitate" is a product after dissolving a drug and a polymer in a solvent or solvent mixture followed by the removal of the solvent or solvent mixture. Sometimes the polymer can be suspended in the solvent or solvent mixture. The solvent may be removed by applying vacuum drying, spray drying, tray drying, lyophilization, and other drying procedures.

The term “solid dispersion” relates to the dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system. This is even more important when it comes to low dose medicines where the homogeneity of the API in the final product is a challenge. A solid dispersion can be used effectively as granulation liquid during wet granulation to obtain granules and enhance the uniformity of the API in the final product, to increase the density of the blend so that it occupies less volume per unit weight for better storage and shipment, to facilitate metering or volumetric dispensing, to reduce dust during granulation process to reduce toxic exposure and process-related hazards, and to improve the appearance of the product. Although the pharmaceutical composition may be in various forms, the preferred solid forms are tablets, capsules and caplets.

A major object of the present invention is to provide a stable composition of Selexipag, which is simple to manufacture by a standard manufacturing process, cost effective, and possess good pharmacotechnical properties, content uniformity and linearity.

Further, in the preparation of Selexipag composition in a tablet form, it is very difficult to obtain a stable composition due to low water solubility of selexipag and its extremely low drug content in the finished dosage form.

It has been surprisingly found that the object of the present invention is achieved by forming a solid dispersion comprising the active ingredient and a binder polymer agent.

The polymer according to the present invention may be one or more water-soluble polymer(s). Water-soluble polymers include but are not limited to, cellulose derivatives, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC)) or ethylcellulose; polyvinylpyrrolidones (PVP); polyethylene glycols (PEG); polyvinyl alcohols (PVA); acrylates, such as polymethacrylate (Eudragit(R) E); and copolymers and derivatives thereof.

Moreover, the polymer can be a pH-dependent enteric polymer. Such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (cellulose acetate phthalate (CAP)), hydroxypropyl methyl cellulose phthalates (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC); hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP).

The pharmaceutical compositions of the present invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients. According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid dosage form compositions (tablet/capsule compositions).

Such ingredients include, but are not limited to, fillers, diluents, binders, compression aids, disintegrants, glidants, lubricants, flavors, colorants, sweetener, film-coating agents, plasticizers and the like.

The optional excipients must be compatible with the active ingredient Selexipag or salt, metabolite or derivative thereof so that it does not interfere with it in the composition.

Moreover, any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredients of the composition, in order to overcome problems associated with unfavorable pharmacotechnical characteristics of that substance, and in order to increase the stability of the drug and the shelf-life of the pharmaceutical product and provide a product exhibiting excellent bioavailability and palatability.

Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, dextrin, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinize starch, modified starch, sucrose, talc, xylitol, maltose, fructose, isomalt, maltodextrin, maltitol and the like. Diluents may be in the range of 10-90 by 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, carboxymethyl cellulose, ethyl cellulose, povidonemaltodextrin, methylcellulose, polydextrose, polyethylene oxide, sodium alginate, starch paste, com starch, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose, glucose, sorbitol, lactose, dextrose. Binders may be in the range of 1-40 by 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, Low- Substituted Hydroxylpropyl Cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate (SLS), sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and the like. Disintegrants may be in the range of 0.1 - 25 by weight % of the total weight of the composition.

Glidants may be selected from calcium silicate, calcium phosphate, metallic lauryl sulphatespowdered 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.

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

The active ingredient according to the present invention may include any crystalline form, amorphous, hydrate, co-crystal, salt, ester, solvate, enantiomer, diastereomer or derivative thereof.

According to the present invention the active ingredient is preferable Selexipag base in crystalline form, and the binder polymer is preferable hydroxypropyl cellulose.

Further, according to the present invention, the weight ratio of the active ingredient Selexipag to the polymer may be in the range from 1 : 1 to 1 :675.

According to the present invention the manufacturing process used for the preparation of a pharmaceutical dosage form for oral administration comprising a solid dispersion of a therapeutically effective quantity of selexipag or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, and Hydroxypropyl Cellulose as a binder polymer as a suspension agent in order to improve stability, dissolution and bioavailability of said active ingredient in the finished dosage form, is provided, wherein said process comprises the following steps:

Step 1 : Dispensing and sieving of the active ingredient and intra-granular excipients: Weight individually the active ingredient selexipag, mannitol, as a first diluent, a portion of the total quantity of maize starch as a second diluent, a portion of the total quantity of Low-Substituted Hydroxypropyl Cellulose, as a disintegrant, and the total quantity of Hydroxypropyl Cellulose, as a binder polymer agent, and sieve through appropriate sieve;

Step 2: Preparation of API suspension for wet granulation: in a suitable mixing vessel dissolve a portion of the total quantity of binder polymer Hydroxypropyl Cellulose in water until a clear solution is obtained and add weighted active ingredient and mix until a homogeneous suspension is obtained; Step 3: Wet granulation: in a high shear mixer granulator add individually the remaining intra- granular excipients of step 1, pre-mix them for suitable time, add in said high shear mixer granulator the active ingredient suspension obtained from step 2, as a granulation liquid and granulate until a homogenized wet mixture is obtained;

Step 5: Sizing: Pass the granules obtained from step 4 to an appropriate sieve;

Step 6: Dispensing and sieving of extra-granular excipients: Weigh individually the remaining quantity of Maize starch as a second diluent and the remaining quantity of Low-Substituted Hydroxypropyl Cellulose as a disintegrant and sieve through appropriate sieve;

9: Compress the homogeneous powder obtained from step 8 under controlled humidity in tablets on a rotary tabletting machine using appropriate punches.

10: Prepare a suspension of coating material in purified water using a stainless-steel tank with a mixing device, and

11: Film The tablets prepared from step 9 are sprayed with the coating suspension from step 10. When the coating is completed, the tablets are collected into labelled drums with polyethylene bags in their inner surface and stored in the bulk products quarantine until the quality controls are finished.

The pharmaceutical compositions according to the present invention are characterized by excellent pharmacotechnical properties, such as hardness, homogeneity, flowability and compressibility. Thanks to these properties, the solid dosage forms prepared by the process according to the present invention exhibit excellent technical characteristics including dissolution rate, hardness, stability and bioavailability.

One of the main objects of the present invention was to prepare a product with acceptable stability. For this reason, the tablets of the present invention were exposed to normal and accelerated stability studies according to the current ICH guidelines.

The results showed that the stability of the present invention was good (e.g. total impurities were not increased throughout normal and accelerated conditions).

The selection of appropriate materials (excipients etc.) should be done carefully in order to avoid any incompatibility problems or non-compliance with EMA and FDA guidelines for inactive ingredients.

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

EXAMPLES

Compatibility studies of Selexipag and Polymer

Prior to evaluating the potential effects of inactive ingredients on the stability of the composition comprising selexipag extensive compatibility studies were carried out for the identification of potential interactions. The compatibility studies were performed and confirmed that Selexipag active ingredient is stable and compatible with Hydroxypropyl Cellulose and as well as a variety of other inactive ingredients. The compatibility of Selexipag with Hydroxypropyl Cellulose was monitored against related substances through stability indicating HPLC method. Example 1: Composition 1 containing Selexipag according to the present invention.

TABLE 1 : Composition 1 of the present invention.

For the purpose of stability profile evaluation of Selexipag, composition 1 containing Selexipag and Hydroxypropyl Cellulose, as preferred polymer, in direct contact with each other was prepared and placed at accelerated conditions and elevated temperature for a time period of one month. The impurity profiles of the prepared composition 1 (Table 2) were monitored at time period T=0 days and T=^:30 (Table 2) days and were placed at accelerated conditions, providing essential information for the stability of Selexipag in presence ofHydroxypropyl Cellulose (HPC) polymer.

TABLE 2: Stability results of Composition 1 of Example 1 at time period T = 0 days

The limit of known impurities of Selexipag is no more than 1.0% and unknown impurities is not more than (NMT) 0.5%.

Composition 1 of Example 1 of the present invention was prepared according to the following process: Based on the desirable composition the appropriate quantity of both active ingredient and preferred polymer was weighed individually, mixed for appropriate time, and transferred into an amber vial. Two vials were prepared for composition 1 with the aim the first to be analyzed immediately after the direct contact of the active ingredient and the polymer and the second one after their exposure to accelerated conditions for a time period of 30 days, in order to identify if they are compatible.

The stability results of composition 1 of Example 1 according to the present invention are presented in Table 3.

TABLE 3: Stability results of Composition 1 of Example 1 at accelerated conditions and time period T = 30 days (Temperature 40±2° C and relative humidity 75±5%.~) The compatibility study verified the use of Hydroxypropyl Cellulose (HPC) as a binder polymer agent and the above data reveal the compatibility between Selexipag and Hydroxypropyl Cellulose.

Example 2 - Compositions 2 - 4 containing 0.2mg / 0.4mg and 1.6mg Selexipag

TABLE 4: Composition 2 - 4 of Example 2 containing 0.2mg / 0.4mg and 1.6mg Selexipag of the present invention. A series of compatibility studies were carried out, challenging the stability performance and dissolution profile of selexipag with various excipients and at various ratio. The excipients of example 2 were the most preferred excipients used in the pharmaceutical composition of Selexipag according to the present invention and were subjected to evaluation: first diluent such as mannitol, second diluent such as Starch Maize, disintegrant such as Low-Substituted Hydroxypropyl Cellulose (LS-HPC), binder such as Hydroxypropyl Cellulose, lubricant such as Magnesium stearate and coating such as Hydroxypropyl-m ethyl cellulose (HPMC) based coating material. Compositions 2- 4 of Example 2 of the present invention (TABLE 4) were prepared according to the following manufacturing process: The intragranular materials selexipag, mannitol, starch maize, Low- Substituted Hydroxypropyl Cellulose, Hydroxypropyl Cellulose, were individually weighed and sieved through appropriate sieve. Subsequently, in a suitable mixing vessel a portion of the total quantity of polymer Hydroxypropyl Cellulose is dissolved in purified water until a clear solution is obtained and Selexipag is added in said mixing vessel and mixed until a homogeneous suspension is obtained. Then, the remaining intra-granular excipients are added in a high shear mixer granulator and premixed for suitable time and granulated by adding the Selexipag suspension as a granulation liquid until a homogenized wet mixture is obtained. The granules thus formed are dried in fluid bed dryer to appropriate loss on drying (LOD), and then sized through suitable sieve. Further, all extra-granular excipients starch maize and Low- Substituted Hydroxypropyl Cellulose are dispensed and sieved through appropriate sieve. Then, the previously formed granules from intragranular materials and the extra-granular excipients are added in a suitable blender and mixed for suitable time. Further, lubricant such as magnesium stearate is added in said blender and mixed with the blend from intragranular and extra-granular excipients for suitable time. The homogeneous powder obtained is compressed under controlled humidity in tablets on a rotary tabletting machine by using appropriate punches. Further, a suspension of coating material (such as Hydroxypropyl Methyl cellulose (HPMC) based) is prepared in purified water using a stainless-steel tank with a mixing device and the prepared tablets are sprayed with said coating suspension.

The produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications.

The stability results of compositions 2 - 4 of Example 2 according to the present invention are presented in Tables 5 -7.

TABLE 5: Stability results of Composition 2 of Example 2 at T=0, at accelerated conditions and time period T = 3 months and T=6 months (Temperature 40±2° C and relative humidity 75±5%)

BRT = Below Reporting Threshold and BQL = Below Quantification Limit

TABLE 6: Stability results of Composition 3 of Example 2 at T=0, at accelerated conditions and time period T = 3 months and T=6 months (Temperature 40±2°C and relative humidity 75±5%)

BQL = Below Quantification Limit TABLE 7: Stability results of Composition 4 of Example 2 at T=0, at accelerated conditions and time period T = 3 months and T=6 months (Temperature 40±2° C and relative humidity 75±5%)

3QL = Below Quantification Limit

Further, the composition according to the present invention comprises a low drug loading in the composition. Thus, the produced tablets were tested for content uniformity of Selexipag.

The results of content uniformity tests ensure the consistency of dosage units and each unit in batch has an active ingredient content within a narrow range around the label claim (TABLE 8).

TABLE 8: Content uniformity results of Compositions 2 - 4 of Example 2 at T=0, at accelerated conditions and time period T = 3 months and T = 6 months (Temperature 40±2° C and relative humidity 75±5%) for all 3 compositions

The acceptance value under content uniformity has been calculated according to European Pharmacopoeia 5.2.

The acceptance value of the first 10 dosage units is less than or equal to LI. When the acceptance value is greater than LI, the next 20 dosage units are tested, and the acceptance value is calculated. Thus, it is considered that the requirements for dosage uniformity are met when the final acceptance value of the 30 dosage units is less than or equal to LI and no individual content of the dosage unit is less than (1 - L2 x 0.01) M nor more than (1 + L2 x 0.01) M in calculation of acceptance value under content uniformity, wherein LI (Maximum allowed acceptance value) = 15.0; L2 (Maximum allowed range for , deviation of each dosage unit tested from the calculated value of M) = 25.0 and M = Reference value.

According to the present invention, the uniformity in the amount of the active substance among dosage units of the pharmaceutical composition comprising a solid dispersion of selexipag can be provided.

According to the present invention the wet granulation approach is employed in order to improve flow and compression characteristics of the active ingredient, and to reduce/prevent segregation of the blend components, improve content uniformity and eliminate excessive amounts of fine particles. Additionally, Selexipag is a BCS class II molecule exhibiting low solubility and high permeability.

Further, solubility studies conducted between polymorph of the Uptravi™ which has been used as reference product and the polymorph selected for the present invention to verify if the two (2) polymorphs have similar solubility profiles.

The polymorph of reference product Uptravi™ is Selexipag crystalline Form I as disclosed in WO20 10/150865.

Selexipag active ingredient according to the present invention is in crystalline form and characterized by its X-ray powder diffraction pattern having peaks, expressed in degrees 20 (±0.2°), at about 3.3°, 11.3° and 23.2°.

The solubility data of Selexipag polymorph of the reference product and of Example 2 according to the present invention are presented in Table 9.

TABLE 9: Solubility data of Composition 2 - 4 of Example 2 at T=0, at accelerated conditions and time period T = 3 months and T=6 months (Temperature 40±2°C and relative humidity 75±5%)

The solubility studies demonstrated that Selexipag polymorph in the present invention exhibits greater solubility than the reference product in all tested medium. This finding means that a medicine product having the polymorph used in the present invention in its composition will provide faster dissolved quantity of Selexipag drug substance when compared with a composition having the polymorph of the reference product..

Taking in consideration that Selexipag API is considered a high permeable drug substance, i.e. meaning that the absolute bioavailability is more than 85% of the dissolved quantity, and due to the fact that Selexipag is a BCS class II drug, it was decided to develop a formulation having a slower dissolution profile compared to the reference product, i.e. f2 similarity factor will not be a prerequisite for comparison with said reference product.

Thus, it has been found that the key ingredient for controlling the release of Selexipag API from a formulation is the type and the level of the binder.

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 Paddle Apparatus was used at rotation speed 75 rpm, in aqueous dissolution medium with various pH values. Moreover, the composition of the present invention should be able to keep constant the Selexipag dissolution release. The dissolution release of Selexipag from the prepared compositions 2 - 4 (see Table 10) was monitored at time period T=0 days, T=3 months and T=6 months (Table 2) months and were placed at accelerated conditions, providing essential information for the stability of Selexipag in presence of Hydroxypropyl Cellulose.

TABLE 10: Dissolution release of Selexipag of Compositions 2 - 4 of Example 2 at T=0, at accelerated conditions and time period T = 3 months and T=6 months (Temperature 40±2° C and relative humidity 75±5%) for all 3 compositions

As it is shown in Table 10, compositions 2 - 4 of Example 2 according to the present invention show a constant dissolution rate of the active substance of the pharmaceutical composition comprising a solid dispersion of selexipag.

Consequently, according to the present invention, a storage-stable pharmaceutical composition comprising a solid dispersion of selexipag is provided, having higher solubility, good storage stability and better handling and processing ability.

Further, the pharmaceutical composition of the present invention comprising a solid dispersion of selexipag with a low drug loading provides good or improved content uniformity and is prepared by simple technological process and on industrial scale.

Moreover, the solid dispersion of Selexipag according to the present invention exhibits higher polymorphic stability at elevated temperatures and increased relative humidity.

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 stable pharmaceutical composition for oral administration comprising a solid dispersion comprising a therapeutically effective quantity of selexipag or a pharmaceutically acceptable salt, or derivative thereof, as an active ingredient and a binder polymer as a suspension agent in order to improve the stability, dissolution and bioavailability of said active ingredient in the finished dosage form.

2. The pharmaceutical composition according to claim 1, wherein the weight ratio of Selexipag or salt and/or derivative thereof to the binder polymer is in the range from 1 : 1 to 1 : 675.

3. The pharmaceutical composition according to claim 1, wherein said active ingredient is selexipag base in crystalline form, amorphous or substantial amorphous form.

4. The pharmaceutical composition according to any of the previous claims, wherein said binder polymer is selected from the group consisting of hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyacrylic acid (PAA), poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), hydroxypropyl methyl cellulose (HPMC), copovidone, hypromellose acetate succinate (AQOAT), poly- acrylates, and mixtures thereof in an amount of 1 to 40% by weight % of the total weight of the composition

5. The pharmaceutical composition according to any of the previous claims, wherein said binder polymer is Hydroxypropyl Cellulose.

6. The pharmaceutical composition according to any of the previous claims, wherein said solid dispersion comprises Selexipag in crystalline form and binder polymer Hydroxypropyl Cellulose as a suspension agent.

7. The pharmaceutical composition according to any of the previous claims, wherein further comprises at least one pharmaceutically acceptable excipient, as diluent, selected from the list consisting of mannitol, starch maize or mixture thereof in an amount from 10 to 90% by weight % of the total weight of the composition.

8. The pharmaceutical composition according to any of the previous claims, wherein it further comprises at least one pharmaceutically acceptable excipient as disintegrant, such Low- Substituted Hydroxypropyl Cellulose in an amount of 0.1 to 25% by weight % of the total weight of the composition.

9. The pharmaceutical composition according to any of the previous claims, wherein it further comprises magnesium stearate as a lubricant.

10. The pharmaceutical composition according to any of the previous claims, wherein said composition further comprises a coating, optionally a Hydroxypropylmethylcellulose based coating.

11. A process for the preparation of a pharmaceutical dosage form for oral administration comprising a solid dispersion of a therapeutically effective quantity of selexipag or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, and a binder polymer as a suspension agent in order to improve stability, dissolution and bioavailability of said active ingredient in the finished dosage form, wherein said process comprises the following steps: Step 1 : Dispensing and sieving of the active ingredient and intra-granular excipients: Weigh individually the active pharmaceutical ingredient (API) selexipag, mannitol, as a first diluent, a portion of the total quantity of maize starch as a second diluent, a portion of the total quantity of Low-Substituted Hydroxypropyl Cellulose, as a disintegrant, and the total quantity of Hydroxypropyl Cellulose, as a binder polymer agent, and sieve through appropriate sieve;

2: for wet in a suitable mixing vessel dissolve a portion of the total quantity of binder polymer Hydroxypropyl Cellulose in purified water until a clear solution is obtained and add weighted active ingredient and mix until a homogeneous suspension is obtained;

3: Wet in a high shear mixer granulator add individually the remaining intra- granular excipients of step 1, pre-mix them for suitable time, add in said high shear mixer granulator the active ingredient suspension obtained from step 2, as a granulation liquid and granulate until a homogenized wet mixture is obtained; the granules obtained from step 3 are dried in fluid bed dryer to appropriate loss on drying (LOD); Pass the granules obtained from step 4 to an appropriate sieve; : Weigh individually the remaining quantity of Maize starch as a second diluent and the remaining quantity of Low-Substituted Hydroxypropyl Cellulose as a disintegrant and sieve through appropriate sieve; In a suitable blender add the granules obtained from step 5 and the extra-granular excipients from step 6 and mix for appropriate time;

8: Lubrication: Weight individually magnesium stearate, as a lubricant, sieve it through appropriate sieve and mix with the blend obtained from step 7 into a blender for appropriate time, and

12. The process for the preparation of a pharmaceutical dosage form according to claim 11, wherein it further comprises two additional steps, namely:

Step 10: Coating suspension: Prepare a suspension of coating material in purified water using a stainless-steel tank with a mixing device, and

Step 11: Film Coating: The tablets prepared from step 9 are sprayed with the coating suspension from step 10. When the coating is completed, the tablets are collected into labelled drums with polyethylene bags in their inner surface and stored in the bulk products quarantine until the quality controls are finished.