WO2020255157A1

WO2020255157A1 - Stable solid dosage form of selexipag and process for preparation thereof

Info

Publication number: WO2020255157A1
Application number: PCT/IN2020/050488
Authority: WO
Inventors: Vijay Joguparthi; Mahesh ANNAM
Original assignee: Aizant Drug Research Solutions Private Limited
Priority date: 2019-06-20
Filing date: 2020-06-02
Publication date: 2020-12-24

Abstract

The present invention relates to stable solid dosage forms of Selexipag and process for preparation of the stable solid dosage for. The present invention also relates to a robust process for preparation of stable solid dosage forms of Selexipag where the dosage form comprises of minor portion of active ingredient and major portion of inactive ingredient. The said composition characteristically uses ratio of intragranular and extragranular excipients for providing a faster dissolution and higher bioavailability profile for the dosage for. Also the present invention provides methods for optimizing the best suitable release profile by using ratio of binder and disintegrant in the intragranular and extragranular portions of the dosage forms.

Description

STABLE SOLID DOSAGE FORM OF SELEXIPAG

AND PROCESS FOR PREPARATION THEREOF

CROSS REFERENCE

This application claims priority to an Indian provisional patent application no. 201941024462, filed June 20, 2019, the contents of which are incorporated herein by reference in their entireties.

FIELD OF INVENTION

The present invention relates to a stable solid dosage form of Selexipag with pharmaceutically acceptable excipients and its method of preparation.

BACKGROUND

Selexipag has the chemical name 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}- N-(methylsulfonyl)acetamide. It has a molecular formula of C₂₆H₃₂N₄O₄S and a molecular weight of 496.62, Selexipag has the following chemical structure:

Selexipag is a selective non-prostanoid IP prostacyclin receptor agonist. It has been developed by Actelion and Nippon Shinyaku for the treatment of arteriosclerosis obliterans, pulmonary hypertension and Raynaud's disease secondary to systemic sclerosis. There are various crystal forms available, few namely are Form I, II and III. Various forms of Selexipag available in the literature are disclosed in U.S. Patentno. 7,205,302,U.S. Patent no. 8,791,122, US 2014-0148469 and US 2014-0155414, which disclose polymorphs of Selexipag, predominantly I, II and III. US10188648B2 discloses solid state forms of Selexipag. W02010/150865A1 discloses three crystalline forms of Selexipag. Selexipag and its synthesis are described in W02002/088084A1. EP2447254 also discloses crystalline forms of Selexipag and their preparation. Indian patent application no 201641024794 discloses various crystalline forms of Selexipag, namely, Form IV, Form V, Form VI, Form VII, Form VII- 1, Form VIII and Form IX.

However, in general, crystalline forms of Selexipag have the disadvantage that they are only poorly soluble, which is reflected by their classification as BCS (Biopharmaceutics Classification System) class II. Poorly soluble, or even non-soluble, active pharmaceutically ingredients (API) generally have the problem that they exhibit a poor, non-sufficient bioavailability upon administration to a subject in need thereof. This poor bioavailability is - inter alia - due to the poor dissolution profile of Selexipag. Also some of the solid state forms tend to convert to other forms during storage and manufacturing process thereby leading to incorrect dosing.

Thus it is known that such crystalline forms, especially under humid conditions or in presence of moisture tend to become unstable. Also Selexipag crystalline form sometimes convert to other forms crystalline or amorphous forms, during formulation development stages when it comes in contact with solvents and excipients used in manufacturing or formulation development process. Further Selexipag being a BCS class II compound exhibits low solubility and high permeability. Its low aqueous solubility affects various formulation paradiagram like the dissolution behaviour, flow property, storage stability and real time processing during preparation of dosage forms.

Since new formulation techniques are continuously being developed, more and more tools for formulating Selexipag become available and a skilled person was motivated to develop new pharmaceutical dosage forms containing Selexipag exhibiting improved properties, e.g. with regard to its solubility and dissolution profile. A few formulations comprising Selexipag are known.

W02017121806A1 discloses amorphous solid dispersion comprising Selexipag. WO2018078383 discloses pharmaceutical composition comprising amorphous Selexipag and premixes thereof. WO2018162527A1 discloses aqueous pharmaceutical composition of Selexipag and their lyophilized forms. WO2018015974A1 discloses Polymorphic forms and amorphous solid dispersion of Selexipag. US20180325895A1 discloses a composition of Selexipag and D-mannitol. Indian patent application no 201621036949 discloses pharmaceutical composition comprising Selexipag premix. Indian patent application numbers 3481/MUM/2015 and 2086/MUM/2015 disclose solid dispersions and amorphous forms of Selexipag. 4305/CHE/2015 discloses amorphous solid dispersion comprising Selexipag and one or more pharmaceutically acceptable carriers.

Further even though amorphous solids have increased solubility and an accelerated dissolution rate in comparison to their crystalline counterparts, crystalline solid forms of an active pharmaceutical ingredient are often preferred for the preparation of pharmaceutical compositions, such as tablets, for various reasons such as stability with respect to the solid form or chemical stability or ease of handling during formulation of a pharmaceutical. As a consequence, slower dissolution and lower bioavailability of the drug are consciously accepted and pharmaceutical compositions, which may not be optimal with regard to these parameters, are produced and marketed.

Further there are very few Selexipag dosage forms available in the art due to the lack of stability of the polymorphic forms during processing or manufacturing of dosage forms. Thus in view of the prior art technical problem, there is still a need for a stable pharmaceutical compositionswith adequate stability comprising Selexipag, which is suitable for production on commercial scale. The inventors in the present invention have however now found that careful selection of process parameters and use of particular excipients in specific manner can provide a stable composition with better release profile of Selexipag from solid state forms.

According to the present invention therefore, there is provided aprocess and a stable solid state dosage form comprising Selexipag, or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable excipientin proportion to the formulation for getting a stable and betterrelease profile of the drug.

SUMMARY OF THE INVENTION

The present invention relates to a stable solid state dosage form of Selexipag, comprising of a therapeutically effective amount of Selexipag or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or additive. In another aspect, the present invention also provides a robust process for preparation of stable Selexipag solid dosage forms. The said process characteristically play role in controlling the stability of solid state forms of Selexipag.

In yet another aspect, the present invention provides a process for preparation of a low dose stable Selexipag dosage form, wherein the said solid dosage form active agent is less than 20% by weight of total weight of the solid oral dosage form, preferably less than 10 % by weight of total weight of the solid oral dosage form.

In a further aspect, the present invention provides a stable solid oral dosage form wherein the active ingredient is present in minor portion by weight of the total dosage form and the additive or excipient is present as major portion by weight of the total dosage form.

In yet another objective the present invention provides an advantageous process for preparation of Selexipag dosage form, which critically improves the dissolution profile of the dosage form. Further the process is optimized to provide best results.

In a further objective the present invention provides a Selexipag solid dosage form with a faster dissolution and higher bioavailability of drug.

The below embodiments as further described in the detail description, provides a better understanding of the invention.

DESCRIPTION OF THE INVENTION

The present disclosure is herein described with reference to embodiments, which form a part here. Other embodiments may be used and/or other changes may be made without departing from the spirit or scope of the present disclosure. The illustrative embodiments described in the description are not meant to be limiting of the subject matter presented here.

The inventors in the present invention have explored the use of various process parameters and steps, for achieving a stable solid dosage form. The inventors have found that stable solid dosage form of Selexipag when produced according to a reliable and robust process comprises of a very small amount of the active ingredient, and a desired stabilizing effect is achieved on the solid state form of Selexipag or its pharmaceutically acceptable salt. Thus, process features and composition components were used for controlling the stability of solid state form in the present invention. The present invention pertains to solid state dosage forms of Selexipag with a) An active agent containing an effective amount of Selexipag or its pharmaceutically acceptable salt; and

b) A pharmaceutically acceptable excipient or additive suitable for the preparation of solid dosage formsby any suitable techniques like dry granulation, wet granulation or direct compression, wherein the active agent in the solid dosage form is present in an amount of less than 20 % by weight of total weight of the solid oral dosage form, preferably less than 10 % by weight of total weight of the solid oral dosage form.

In another embodiment the amount of active ingredient may be present in an amount of 0.001 to 10 % by weight of total weight of the solid oral dosage form.

In a further embodiment the amount of active ingredient in the solid dosage form may be present in an amount of 100 microgram (meg) to 2000 microgram (meg), more preferably in an amount of 200 meg, 400 meg, 600 meg, 800 meg, 1000 meg, 1200 meg, 1400 meg and 1600 meg.

In another embodiment the present invention provides stable solid dosage form for effective treatment of pulmonary arterial hypertension or to delay disease progression and reduce the risk of hospitalization for pulmonary arterial hypertension and any other related conditions thereof.

An“effective amount” is the amount of a compound necessary to result in a desired physiological change in the subject. Effective amounts disclosed herein effectively treats pulmonary arterial hypertension or delays progression and reduce the risk of hospitalization for pulmonary arterial hypertension. For example, an effective amount may result in a delay in disease progression and reduce the risk of hospitalization for pulmonary arterial hypertension (PAH).

In yet another embodiment of the present invention, there is provided a process of forming a stable solid dosage form of Selexipag or its pharmaceutically acceptable salt, wherein the solid dosage form is comprisingof less than 10% by weight of Selexipag or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable additive wherein the process comprises the steps of: i. blending the Selexipag or the salt thereof and at least one pharmaceutically acceptable additive to form a mixture;

ii. subjecting the mixture to suitable granulation technique;

iii. milling the granulate followed by drying and sizing using suitable sizing technique; and

iv. mixing with suitable lubricant followed by compressing and coating.

In yet another embodiment the stable solid dosage form of present invention may be coated or uncoated, and wherein the solid dosage form is coated, it may be film coated, enteric coated, non-enteric coated or coated with any other pharmaceutically acceptable coating.

A solid oral dosage form according to the invention comprises additives conventional in the dosage form in question. Tabletting aids, commonly used in tablet formulation can be used and reference is made to the extensive literature on the subject as in Fiedler's "Lexicon der Hilfstoffe", 4th Edition, ECV Aulendorf 1996, which is incorporated herein by reference. These include but are not limited to disintegrants, binders, lubricants, glidants, stabilising agents, fillers or diluents, surfactants, coating materials, polymers and the like.

In a further embodiment the stable solid dosage form of present invention comprises of at least one pharmaceutically acceptable additive selected from diluent, binder, lubricants, granulating agent, disintegrants, glidants, sweeteners, vehicles, polymers, flavors, anti- adherents and fillers.

One or more of these pharmaceutically acceptable additives can be selected and used by the skilled artisan having regard to the particular desired properties of the solid oral dosage form by routine experimentation and without any undue burden.

The amount of each type of additive employed, e.g. glidant, binder, disintegrant, filler or diluent, granulating fluid and lubricant may vary within ranges conventional in the art.

In a further embodiment the present invention provides a solid oral dosage form wherein the active ingredient is present in minor portion by weight of the total dosage form and the additive or excipient is present as major portion by weight of the total dosage form.

The absolute amounts of each additive and the amounts relative to other additives is similarly dependent on the desired properties of the solid oral dosage form and may also be chosen by a person skilled in the art by routine experimentation without undue burden. For example, the solid oral dosage form may be chosen to exhibit accelerated and/or delayed release of the active agent with or without quantitative control of the release of active agent.

Further the quantitative control of the release of the active agent can also be achieved by conventional techniques known in the art. Such dosage forms are known as coated tablets, matrix tablets, press-coated tablets, multilayer tablets and the like.

In a further embodiment the present invention provides a solid dosage form wherein the Selexipag or its pharmaceutically acceptable salt may also be combined with any other suitable anti hypertensive drug or drug for treatment of pulmonary arterial hypertension.

In yet another embodiment the solid oral dosage form according to the present invention is wherein the active agent consists entirely of Selexipag or a pharmaceutically acceptable salt thereof, it is preferred if the active agent is present in an amount of from 100 microgram (meg) to 2000 microgram (meg), more preferable 200 to 1600 meg, e.g. 200 meg, 400 meg, 600 meg, 800 meg, 1000 meg, 1200 meg, 1400 meg or 1600 meg.

In a preferred embodiment there is provided a process of making the solid oral dosage forms as hereinabove described comprising the steps of i) grinding the active agent and pharmaceutically acceptable additives, ii) subjecting a mixture of the grounded active agent and additives to granulation followed by milling and sizing iii) Lubricating the mixture followed by compression and coating to form the solid oral dosage form.

In yet another embodiment the process for preparation of the present invention stable solid dosage form comprises: co-sifting Selexipag or its pharmaceutically acceptable salt with suitable diluents and binders through mesh;

mixing or dry mixing the co-sifted mixture in suitable mixer or granulator;

granulating the mixed material using suitable granulating technique;

milling using suitable milling technique followed by drying and sizing;

lubricating the sized granules using suitable lubricating agent followed by compression and coating.

In yet another embodiment the active agent and the additives can be milled either individually or together. Also the grounded or sized particles may optionally at this stage be sieved and mixed according to known methods. In yet another embodiment the diluent and binder can be same or different in both intra and extragranular portion of the dosage form.

In a further embodiment the presence of binder, diluent or disintegrant in the intragranular portion of the dosage form, play key role in the dissolution profile of the drug. In yet another related embodiment the presence of binder, diluent or disintegrant in the extragranular portion of the dosage form, play key role in the dissolution profile of the drug.

In a most preferred embodiment the presence of binder, diluent or disintegrant in a proportionate distribution across both intra and extragranular portion of the dosage form is the key factor in promoting an advantageous dissolution profile. In a further embodiment of the present invention, the ratio of intragranular and extragranular excipient is 1:50 to 50:1, preferably 1:10 to 10:1.

In a further embodiment of the present invention, the ratio of intragranular and extragranular binder is 1:50 to 50:1, preferably 1:10 to 10:1.

In a further embodiment of the present invention, the ratio of intragranular and extragranular disintegrant is 1 :50 to 50: 1 , preferably 1 : 10 to 10: 1.

In a further embodiment, the present invention also encompasses the use of binder which can also be used as disintegrant in the formulation.

In yet another embodiment, the present invention provides characteristically advantageous solid dosage form of Selexipag with intragranular binder or disintegrant in a range of 1-30% by weight of total composition, preferably 1-15%, more preferably 1-10%.

In yet another embodiment, the present invention provides characteristically advantageous solid dosage form of Selexipag with extragranular binder or disintegrant in a range of 1-30% by weight of total composition, preferably 1-15%, more preferably 1-10%.

In yet another embodiment, the present invention provides characteristically advantageous solid dosage form of Selexipag comprises of intragranular and extragranular binder or disintegrant in a range of with 1-30% by weight of total composition, preferably 1-15%, more preferably 1-10%. In yet another embodiment, the present invention provides characteristically advantageous solid dosage form of Selexipag comprises of intragranular and extragranular binder or disintegrant equally distributed in both intragranular and extragranular part of the dosage form. In yet another embodiment, the present invention provides characteristically advantageous solid dosage form of Selexipag comprises of intragranular and extragranular binder or disintegrant wherein the distribution of the said excipients is comparatively higher in intragranular and lower in extragranular part of the dosage form respectively.

In yet another embodiment, the present invention provides characteristically advantageous solid dosage form of Selexipag comprises of intragranular and extragranular binder or disintegrant wherein the distribution of the said excipients is comparatively lower in intragranular and higher in extragranular part of the dosage form respectively.

In yet another preferred embodiment, the present invention solid dosage form of Selexipag comprises 2-10 % intragranular binder or disintegrant and 0.5-1.5% extragranular binder or disintegrant.

In yet another embodiment, the binder, diluent or disintegrant used in the intragranular or extragranular portions of the composition is selected from various starches and cellulose derivatives, preferably corn starch and hydroxy propyl cellulose.

In a further embodiment, the present invention provides solid dosage form of Selexipag which can comprise crystalline, amorphous or any other polymorphic forms of Selexipag.

In a most preferred embodiment, the present invention provides a stable solid oral dosage form of Selexipag.

As used herein, the term "stable" means that the formulation has an acceptable pharmaceutical shelf life of at least 12 months, preferably at least 24 months, when stored at 25 °C and at a relative humidity of 60% in a conventional pharmaceutical packaging. Thus in one embodiment of the invention, the formulations are chemically and physically stable and have a shelf life of at least 12 months, preferably at least 24 months, when stored at 25 °C and at a relative humidity of 60% in a conventional pharmaceutical packaging. In yet another embodiment, the present invention provides a tablet or pellet composition of Selexipag with at least one lipophilicmaterial or polymer and having delayed or modifiedor controlled drug release.

In another embodiment the present invention provides a process for manufacturing the composition comprising of following steps: i. Weighing accurate quantities of raw material and API required for the manufacturing;

ii. Co-sifting Selexipag and mannitol through suitable mesh;

iii. Co-sifting Hydroxy propyl cellulose and methacrylic acid Copolymer through suitable mesh;

iv. Co-sifting the material from step ii) & iii) through suitable mesh;

v. Loading the sifted material from step iv) in to a suitable Rapid mixer granulator and mixing for suitable period of time at slow impeller speed;

vi. Granulating the mixed material of step v) with suitable granulating agent;

vii. Milling the granulate from step vi) followed by drying the milled mass;

viii. Milling the dried mass of step vii) followed by sizing in suitable mill;

ix. Co-sifting extragranular portion of mannitol and hydroxypropyl cellulose;

x. Blending the sized material from step viii) and the sifted material from step ix) in a suitable blender;

xi. Sifting magnesium stearate through suitable mesh followed by blending with blended material from step x);

xii. Compressing the lubricated blend from step xi) followed by applying suitable coating.

The Selexipag used in the present invention is selected from crystalline, amorphous, anhydrous, or any other suitable form, solvate or pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the invention can be formed by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct blending & filling/compression, double compression, extrusion spheronization, layering and the like. The composition or formulation may be coated or uncoated. Coating of compositions such as tablets and caplets is well known in the art. Pharmaceutically acceptable excipients may be utilized as required for conversion of the granules into the final pharmaceutical dosage forms and include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, sweeteners, taste modifying agents, flavoring agents and other additives that are commonly used in solid pharmaceutical dosage form preparations.

Non limiting examples of excipients that can be used in the composition are:

Diluents:

Various useful fillers or diluents include but are not limited to starches, lactose, mannitol, cellulose derivatives, confectioner's sugar and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™, Pharmatose™ and others. Different starches include but are not limited to maize starch, potato starch, rice starch, corn starch, wheat starch, pregelatinized starch and starch 1500, starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch and others. Different cellulose compounds that can be used include crystalline celluloses and powdered celluloses. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, PF1112 microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol (Pearlitol™ SD200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Binders:

Various useful binders include but are not limited to hydroxypropyl celluloses, also called F1PC (Klucel™ LF, Klucel EXF) and useful in various grades, hydroxypropylmethylcelluloses, also called hypromelloses or F1PMC (Methocel™ ) and useful in various grades, polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP- K29, PVP-K30, and PVP-K90), Plasdone™ S-630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (Carbopol.TM.), methylcelluloses, polymethacrylates, methacrylic acid copolymer and starches.

Granulating fluids: Various useful binders include but are not limited to water, ethanol and iso-propanol and methylene chloride either alone or in combination or Granulating liquids may be used alone or with dissolved binders.

Disinte grants:

Various useful disintegrants include but are not limited to carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidones, examples of commercially available crospovidone products including but not limited to hydroxypropylcellulose,crosslinkedpovidone, Kollidon™ CL, Polyplasdone™ XL, XI- 10, and INF-10 and low-substituted hydroxypropylcelluloses. Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33. Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches.

Stabilizers:

Various useful stabilizers include basic inorganic salts, such as but not limited to basic inorganic salts of sodium, potassium, magnesium and calcium. Examples of basic inorganic salts of sodium are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like. Examples of basic inorganic salts of potassium are potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, and the like. Examples of basic inorganic salts of magnesium are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg₆Al₂(0H)16.C03.4H20], aluminum hydroxide - magnesiumi2.5MgO.Al2O3.xH2O], and the like. Examples of basic inorganic salts of calcium include precipitated calcium carbonate, calcium hydroxide, and the like.

Surf ace- Active Agents:

Useful surface-active agents include non-ionic, cationic and anionic surface-active agents. Useful non-ionic surface-active agents include ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (SPAN™) and polyhydroxyethylenically treated sorbitan esters (TWEEN™), aliphatic alcohols and PEG ethers, phenol and PEG ethers. Useful cationic surface-active agents include quaternary ammonium salts (e.g. cetyltrimethylamrnonium bromide) and amine salts (e.g. octadecylamine hydrochloride). Useful anionic surface-active agents include sodium stearate, potassium stearate, ammonium stearate, and calcium stearate, triethenolamine stearate, sodium lauryl sulphate, sodium dioctylsulphosuccinate, and sodium dodecylbenzenesulphonate. Natural surface-active agents may also be used, such as for example phospholipids, e.g. diacylphosphatidylglycerols, diaceylphosphatidylcholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as for example soybean lecithin and egg yolk.

Lubricants:

An effective amount of any pharmaceutically acceptable tableting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and combinations thereof. Glidants:

One or more glidant materials, which improve the flow of powder blends and minimize dosage form weight variation, can be used. Useful glidants include but are not limited to silicon dioxide, talc and combinations thereof.

Coloring Agents: Coloring agents can be used to color code the compositions, for example, to indicate the type and dosage of the therapeutic agent therein. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides, zinc oxide, combinations thereof, and the like. Flavoring agents:

The flavoring agents may comprise one or more synthetic or natural flavouring or aromatizing agents. Flavoring agents may be selected from essential oils including distillations, solvent extractions, mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavour of the fruit, e.g., strawberry, raspberry and black currant; artificial and natural flavours of brews, liquors and other possible flavours.

Sweetening agents:

Sweetening agents are added essentially to improve the taste, and comprise one or more synthetic or natural sugars, i.e., any form of carbohydrates suitable for use as sweetener, as well as so called artificial sweeteners such as saccarin, sodium saccarin, aspartame, e.g., NutraSweet.RTM., acesulfame K or acesulfame, potassium acesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcone, alitame, miraculin, monellin, stevside.

Useful additives for coatings include but are not limited to plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents, suitable coatings may be done as film coating with Opadry.

The above described excipients can be used in different aspects, like a component which is used as diluent may be used as filler, binder or disintegrant or as any other functional component. A person skilled in the art will acknowledge that the use of an excipient for various functions is well within the scope of the present invention.

EXAMPLES

The following examples are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter. A person skilled in the art will readily recognize the various modifications and variations that may be performed withoutaltering the scope of the present invention. Such modifications and variations are encompassed within the scope of the invention and the examples do not in any way limit the scope of the invention.

Example 1: Selexipag Tablet Dosage Form(200 meg)

Procedure: i. Weighing accurate quantities of excipient and API required for the manufacturing; ii. Co-sifting Selexipag and mannitol through suitable mesh;

iv. Co-sifting the material from step ii) & iii) through suitable mesh;

vi. Granulating the mixed material of step v) with dehydrated alcohol;

vii. Milling the granulate from step vi) followed by drying the milled mass;

viii. Milling the dried mass of step vii) followed by sizing in suitable mill;

ix. Co-sifting extragranular portion of mannitol and hydroxypropyl cellulose;

Example 2: Selexipag Tablet Dosage Form (1600 meg)

Example 3: Qualitative composition of wet granulation approach

Table-1: Comparative in-vitro dissolution profiles of trial batch with Uptravi®

Example 4: Trial batches were taken to study the effect of level of Corn starch in intragranular and extragranular portions of the compositions; the manufacturing formula is shown below:

Table-2: Comparative in-vitro dissolution profiles of trial batch to study the impact of level of Corn starch in the formulation:

Table-2 clearly shows that there is significant effect of corn starch concentration in intragranular and extragranular portions of the composition. The release of drug is reduced when corn starch is present in extragranular portion, thus in the formulation process of preparation is playing critical role in the dissolution profile of the drug, thereby affecting the therapeutic and pharmacokinetic aspects of the dosage form.

Example 5: Trial batches were taken to study the effect of level of Hydroxypropyl cellulose in intragranular, extragranular portions and both intragranular and extragranular portions of the compositions; the manufacturing formula is shown below:

Table-3: Comparative in-vitro dissolution profiles of trial batch to study the impact of level of Hydroxypropyl cellulose in the formulation:

Table-3 shows the impact of hydroxypropyl cellulose concentration in intragranular and extragranular portions of the composition. The release of drug is comparatively reduced when HPC is present in intragranular or extragranular portion, however when there is a proper ratio based distribution of HPC in both intra and extragranular portions there is significant improvement in the dosage form drug release, thus in the formulation process of preparation is playing critical role in the dissolution profile of the drug, thereby affecting the therapeutic and pharmacokinetic aspects of the dosage form. Example 6: Manufacturing formula of Direct Compression Process

Table-4: In-vitro dissolution profiles of trial batch with Direct Compression approach:

Example 7: Manufacturing formula of Dry Granulation Process

Table-5: In-vitro dissolution profiles of trial batch with Dry granulation approach:

Table-2, 4 & 5 shows the impact of various tabletting process viz., wet granulation, direct compression and dry granulation approaches on the final composition and its dissolution profile. The release of drug is comparatively faster in wet and dry granulation approaches, whereas the release is slower in case of direct compression. However the final release of the drug towards the end point of dissolution is similar in all the three approaches. This depicts that the manufacturing / tabletting process also plays role in the release pattern of the drug from the formulation.

Claims

CLAIMS:

1. A stable solid dosage form of Selexipag or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient.

2. The stable solid dosage form as claimed in claim 1, wherein the said pharmaceutically acceptable excipient is selected from one or more of diluents, binders, stabilizers, lubricants, glidant, disintegrating agents, surfactants, sweeteners, taste modifying agents, flavoring agents and other additives commonly used in solid pharmaceutical dosage form preparations.

3. The stable solid dosage form as claimed in claim 1, wherein the said dosage form comprises of intragranular and extragranular components and the said pharmaceutically acceptable excipient may be present either in intragranular part or extragranular part or in both intragranular and extragranular part.

4. The stable solid dosage form as claimed in claim 1 , wherein the said intragranular part of the dosage form comprises of at least one binder or disintegrant in a concentration range of about 1 -30% by weight of total composition.

5. The stable solid dosage form as claimed in claim 1 , wherein the said extragranular part of the dosage form comprises of at least one binder or disintegrant in a concentration range of about 0.5-30% by weight of total composition.

6. The solid dosage form as claimed in claim 1 , wherein the said dosage form comprises of intragranular and extragranular components and the said pharmaceutically acceptable excipient is distributed both in intragranular and extragranular part in a ration of 1:50 to 50: 1.

7. The stable solid dosage form as claimed in claim 1, wherein the said dosage form is a delayed release, modified release or controlled release dosage form.

8. The stable solid dosage form as claimed in claim 1, wherein the said dosage form is prepared by dry granulation, wet granulation, hot melt granulation, direct blending & filling/compression, double compression, extrusion spheronization or layering.

9. A process for preparation of a solid dosage form of Selexipag or its pharmaceutically acceptable salt with at least on pharmaceutical acceptable excipient, wherein the said process comprises of: i. weighing accurate quantities of excipient and Selexipag or its pharmaceutically acceptable salt, required for preparation of said solid dosage form;

ii. co-sifting Selexipag or its pharmaceutically acceptable salt with suitable diluents and binders through mesh;

iii. mixing or dry mixing the co-sifted mixture from step ii) in suitable mixer or granulator;

iv. granulating the mixed material from step iii) using suitable granulating technique;

v. milling the granulated composition from step iv) using suitable milling technique followed by drying and sizing;

vi. lubricating the sized granules from step v) using suitable lubricating agent followed by compression and coating.

10. The process as claimed in claim 9, wherein the excipient used in the process are pharmaceutically acceptable excipient used in the manufacturing of solid dosage forms comprising diluent, binders, carriers, disintegrant, surfactant, lubricants, glidant, solvent or their combinations.

11. The process as claimed in Claim 9, wherein the excipient used in the said process are distributed both in intragranular and extragranular portion, wherein the ratio of intragranular and extragranular excipient is 1:50 to 50: 1.

12. The stable solid dosage form as claimed in claim 1 , wherein the said dosage form gives a faster dissolution and higher bioavailability of the drug.

13. A method for effective treatment of pulmonary arterial hypertension or to delay disease progression using a stable solid dosage form of Selexipag.

14. The method as claimed in claim 13, wherein the said method comprises of administering a Selexipag dosage form as claimed in claim 1, wherein the said dosage form is having faster dissolution and higher bioavailability of the drug.

15. The stable solid dosage form as claimed in claim 1 , wherein the said dosage form comprises of intragranular and extragranular binder or disintegrant or their combinations distributed in ratios which provide an improved bioavailability of the said dosage form.