DESC:FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising an endothelin receptor antagonist (ERA) as an active agent, process of preparation thereof and method of using the same. Particularly, the present invention relates to a pharmaceutical composition comprising Macitentan, process of preparation thereof and method to treat Pulmonary Arterial Hypertension to delay disease progression.

BACKGROUND OF THE INVENTION

Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid peptides produced and active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332:411). Endothelins are potent vasoconstrictors and important mediators of cardiac, renal, endocrine and immune functions (McMillen MA et al.: J Am CollSurg (1995) 180:621). They participate in bronchoconstriction and regulate neurotransmitter release, activation of inflammatory cells, fibrosis, cell proliferation and cell differentiation (Rubanyi GM et al.: Pharmacol Rev (1994) 46:328).

In contrast, the ETB receptor has equivalent affinity for the three endothelin isopeptides and binds the linear form of endothelin, tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991) 178:248). This receptor is located in the vascular endothelium and smooth muscles, and is also particularly abundant in lung and brain. The ETB receptor from endothelial cells mediates transient vasodilator responses to ET-1 and ET-3 through the release of nitric oxide and/or prostacyclin whereas the ETB receptor from smooth muscle cells exerts vasoconstricting actions (Sumner MJ et al.: Brit J Pharmacol (1992) 107:858). ETA and ETB receptors are highly similar in structure and belong to the superfamily of G-protein coupled receptors.

A pathophysiological role has been suggested for ET-1 in view of its increased plasma and tissue levels in several disease states such as hypertension, pulmonary hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive heart failure, renal failure, migraine and asthma. As a consequence, endothelin receptor antagonists have been studied extensively as potential therapeutic agents. Endothelin receptor antagonists have demonstrated preclinical and/or clinical efficacy in various diseases such as cerebral vasospasm following subarachnoid hemorrhage, heart failure, pulmonary and systemic hypertension, neurogenic inflammation, renal failure and myocardial infarction.

Furthermore, the contribution of differing ETA / ETB receptor blockade to the clinical outcome is not known. Thus, tailoring of the physicochemical and pharmacokinetic properties and the selectivity profile of each antagonist for a given clinical indication is mandatory. So far, no endothelin receptor antagonists with a pyrimidine core structure containing a sulfamideunit have been reported.

Macitentan is an endothelin receptor antagonist that prevents the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro.

The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide. It has a molecular formula of C19H20Br2N6O4S and a molecular weight of 588.27. Macitentan is achiral and has the following structural formula:

Macitentan is currently marketed as Opsumit® tablets and indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. The tablet formulation contains 10 mgof Macitentan and the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A. The tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum.

US Patent number 8367685disclosesan oral preparation which comprises Macitentan, b) a filler, consisting of lactose monohydrate with microcrystalline cellulose, c) a disintegrant, consisting of sodium starch glycolate or a combination of sodium starch glycolate and polyvinylpyrrolidone, d) a surfactant, consisting of a polysorbate, in a total amount of 0.1 to 1% in weight based on the total weight of the pharmaceutical composition, and e) a lubricant, consisting of magnesium stearate. Further, US Patent number 9265762 disclosesan oral preparation which comprises Macitentan, b) a filler, consisting of lactose monohydrate with microcrystalline cellulose, c) a disintegrant, consisting of sodium starch glycolate or a combination of sodium starch glycolate and polyvinylpyrrolidone, d) a surfactant, consisting of a polysorbate, in a total amount of 0.1 to 3% in weight based on the total weight of the pharmaceutical composition, and e) a lubricant, consisting of magnesium stearate. The major objective of the above said patents was to provide stable pharmaceutical compositions comprising Macitentan, or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof. It was stated in the prosecution of the said patents that with the composition containing 0.2% of surfactant particularly polysorbate has superior stability compared to the composition containing commonly used surfactant like sodium lauryl sulfate or composition without surfactant.

Inventors of the present invention have endeavored to develop the stable composition of Macitentan which are economical and commercially viable and which attributes faster disintegration, comparable dissolution and bioavailability with respect to the marketed product Opsumit® (Macitentan).

SUMMARY OF THE INVENTION

An aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an endothelin receptor antagonist as an active agent(s), oneor more filler(s), one or more disintegrant(s), a surfactantand a lubricant.

An aspect of the present invention provides a pharmaceutical composition comprising therapeutically effective amount of macitentan as an active agent(s), oneor more filler(s), one or more disintegrant(s), a surfactantand a lubricant.

An aspect of the present invention provides a pharmaceutical composition comprising: (a) macitentan or pharmaceutically acceptable salt, solvates, hydrates or morphological forms thereof, (b) a filler consisting of lactose, (c) one or more disintegrant, (d) a surfactant, and (e) a lubricant.

An aspect of the present invention provides a oral solid dosage form comprising: (a) macitentan or pharmaceutically acceptable salt, solvates, hydrates or morphological forms thereof, (b) a filler consisting of lactose, (c) one or more disintegrant, (d) a surfactant, and (e) a lubricant.

An aspect of the present invention provides a pharmaceutical composition comprising: (a) macitentan or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof, (b) a filler consisting of lactose, in a total amount of 10% to 98% by weight of the composition, (c) one or more disintegrant, in a total amount of 0.5% to 20% by weight of the composition, (d) a surfactant, in a total amount of 0.1% to 5% by weight of the composition, and (e) a lubricant.

An aspect of the present invention provides a pharmaceutical composition comprising macitentan or pharmaceutically acceptable salt, solvates, hydrates or morphological forms thereof, prepared by a process comprising the following steps:
(a) combining macitentan with lactose;
(b) adding one or more other pharmaceutically acceptable excipients and;
(c) formulating into an oral solid dosage form.

An aspect of the present invention relates to a method of treating pulmonary arterial hypertension comprising the administration to a patient in need thereof,a pharmaceutical composition comprising: (a) macitentan or pharmaceutically acceptable salt, solvates, hydrates or morphological forms thereof, (b) a filler consisting of lactose, (c) one or more disintegrant, (d) a surfactant, and (e) a lubricant.

An aspect of the present invention relates to a method of using a pharmaceutical composition of macitentan to treat pulmonary arterial hypertension (PAH, WHO Group I), and to delay disease progression.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, the term “Macitentan” unless indicated otherwise in the entire specification refers to Macitentanin the form of free base or its pharmaceutically acceptable salt, polymorph, amorphous, crystalline, isomer, derivatives, hydrate,solvate, prodrug or combination thereof. Preferably Macitentanis in the form of free base.The phrase “substantially pure polymorphic form of macitentan or its salt thereof”, unless otherwise specified is to be understood as a substance free of other polymorphic and/or pseudopolymorphic forms at amounts detectable with typical analytical methods such as X-ray powder diffraction and/or solid state infrared absorption, i.e. containing less than 10%, more preferably less than 5% and most preferably less than 1% of other polymorphic and/or pseudopolymorphic forms.

The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug (e.g. macitentan), which is sufficient to elicit an appreciable biological response when administered to the patient.

Macitentan with specific particle size distribution and surface area provide a fast dissolution of the active ingredient. This helps in achieving stable composition of the present invention while maintaining desired properties such as solubility and bioavailability. Particle size distribution may be described using quantities such as D90% and D50%. As used herein, “particle size distribution” means the cumulative volume size distribution of equivalent spherical diameter as determined by Malvern mastersizer particle size analyzer. According to the present invention, Macitentan has particle size distribution having a D90% less than 200 microns and D50% less than 150 microns and/ or surface area less than about 5m2/ gm. Preferably, Macitentan has particle size distribution having a D90% less than 150 microns and D50% less than 100 microns. More preferably, Macitentan has particle size distribution having a D90% less than 100 microns and D50% less than 50 microns. Most preferably, Macitentan has particle size distribution having a D90% less than 80 microns and D50% less than 30 microns.The term “particle size” unless indicated otherwise in the specification relates to particles of Macitentan free base as well as pharmaceutically acceptable salt, Polymorph, amorphous, crystalline, anhydrous, esters, isomer, hydrate¸ prodrug, solvates or its derivatives thereof.

The term “composition” or “pharmaceutical composition” or “dosage form” as used herein synonymously include solid dosage forms such as granules, multiunit particulate system (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.

The term “excipient” means a pharmacologically inactive component such as a diluent, disintegrant, carrier, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. “Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical formulation other than the active ingredient Macitentan. Excipients may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance bioavailability, enhance patient acceptability etc. Pharmaceutically acceptable excipient(s) includes, but not limited to, one or more diluent or filler, binder, disintegrant, lubricant, glidant, compression aid, color, sweetener, preservative, surfactant, suspending agent, dispersing agent, film former, flavor, printing ink, and any other excipient known to the art for making pharmaceutical formulation. According to the present invention a particular excipient may perform multiple roles in the pharmaceutical composition, for example, it can act both as a binder and filler,or as a binder, filler and disintegrant.

Diluent/Filler increases the bulk of the composition. Diluents according to the present invention are selected from, but not limited to, sugar such as lactose, sucrose, dextrose, mannose, fructose, galactose; sugar alcohol such as sorbitol, mannitol, erythritol, xylitol, lactitol; starlac, starch, modified starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, calcium sulfate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, magnesium carbonate, magnesium oxide, magnesium aluminometasilicate and the like used either alone or in combination thereof. The diluent may be used in the range of about 10-98% by weight of the composition.

Binder holds the ingredients together in the composition. Exemplary binders are selected from, but not limited to, cellulose and its derivatives including ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; gelatin, liquid glucose; starch and its derivatives (e.g. corn starch); hydrocolloids; sugars; polyvinyl pyrrolidone, sodium alginate, acacia, alginic acid, tragacanth, xanthan, used either alone or in combination thereof. The binder may be used in the range of about 0-10% by weight of the composition.

Disintegrants according to the present invention are selected from, but not limited to, cellulose and its derivatives including low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, sodium starch glycolate, ion-exchange resins, starch and modified starch including pregelatinized starch, formalin-casein, used either alone or in combination thereof. The disintegrant may be used in the range of about 0.5-20% by weight of the composition.

Lubricant and glidant aid are used in the processing of powder material. Exemplary lubricants are selected from, but not limited to, calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, and zinc stearate, used either alone or in combination thereof. Exemplary glidants include, but not limited to, talc, silicon dioxide, cornstarch and the like used either alone or in combination thereof.

Surfactant according to the invention include but are not restricted to one or more of the following: sodium lauryl sulphate, polysorbates (commercially available as Tween®), polyethylene polyoxypropylene polymers (Pluronic F65), polyoxylethylene stearates (MYRJ), dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters (commercial available from Nikko Chemicals), polyoxyethylene C1-4-alkyl ethers, sucrose monoesters and lanolin esters, ethers, used either alone or in combination thereof. Preferably, sodium lauryl sulphate is used as surfactant.

The phrase “Disease progression” elsewhere used in the specification relates to death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment).

The phrase “medicinal package” unless indicated otherwise in the entire specification refers to bottle or blister pack or pouch or any corresponding packing known to a person skilled in the art in which the dosage form or the medicinal preparation is packed with or without a desiccant.

The term “desiccant” unless indicated otherwise in the entire specification refers to a substance used to remove/suppress/decrease the odor/smell or to absorb moisture which prevents degradation/decomposition of the active agent(s). The desiccant may be placed in the internal space of the medicinal package, irrespective of any particular limit, so long as the amount is sufficient to remove the odorous material, that is, sufficient to suppress or reduce the smell. The amount of the desiccant can vary depending on kind or shape of the desiccant, distance from the medicinal preparation capable of giving out smells, amount of the compound giving out smells, type of formulation, volume of the space where the medicinal preparation and the desiccant are placed, amount of the existing or produced odorous material, preservation condition of the medicinal package.

In an embodiment of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of an endothelin receptor antagonist as an active agent(s), one or more filler(s), one or more disintegrant(s), a surfactant and a lubricant.

In an embodiment of the present invention relates toa pharmaceutical composition comprising therapeutically effective amount of macitentan as an active agent(s), oneor more filler(s), one or more disintegrant(s), a surfactantand a lubricant.

In an embodiment of the present invention relates to a pharmaceutical composition comprising therapeutically effective amount of macitentan as an active agent(s), a filler consisting of lactose, one or more disintegrant(s), a surfactant in an amount of about 0.1 to 5% in weight based on the total weight of the pharmaceutical composition and a lubricant.

In an embodiment the present invention relates to apharmaceutical composition comprising therapeutically effective amount of macitentan as an active agent(s), a filler consisting of lactose, one or more disintegrant(s), a surfactant is selected from polysorbates, sodium lauryl sulphate, polyethylene polyoxypropylene polymers, polyoxylethylene stearates, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene C1-4 alkyl ethers, sucrose monoesters, lanolin esters and ethers, in an amount of about 0.1 to 5% in weight based on the total weight of the pharmaceutical composition, and a lubricant.

In an embodiment the present invention relates to a pharmaceutical composition comprising: (a) macitentan or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof, (b) a filler consisting of lactose, in a total amount of 10% to 98% by weight of the composition, (c) one or more disintegrant, in a total amount of 0.5% to 20% by weight of the composition, (d) a surfactant, in a total amount of 0.1% to 5% by weight of the composition, and (e) a lubricant.

In an embodiment of the present invention relates to a pharmaceutical composition comprising macitentan as an active agent in the form of free base, salt, polymorph, amorphous, crystalline, anhydrous, ester, isomer, hydrate, solvate, prodrug or its derivatives.

In an embodiment of the present invention relates to a pharmaceutical composition comprising macitentan as a free base crystalline form I.

In an embodiment of the present invention relates to a pharmaceutical composition comprising crystalline macitentan free base having an X-ray powder diffraction pattern showing peak maxima at 2 theta/° values of 11.4±0.2, 13.0±0.2, 16.1±0.2, and 25.4±0.2 when a radiation wavelength of 1.5419 Å is used.

In an embodiment of the present invention relates to apharmaceutical composition comprising macitentan as an active agent with a particle size distribution having a D90% less than 200 microns and D50% less than 150 microns.

In an embodiment of the present invention relates to apharmaceutical composition comprising macitentan as an active agent with a particle size distribution having a D90% less than 150 microns and D50% less than 100 microns.

In yet another embodiment of the present invention relates to apharmaceutical composition comprising macitentan as an active agent with a particle size distribution having a D90% less than 100 microns and D50% less than 50 microns.

In yet another embodiment of the present invention relates to apharmaceutical composition comprising macitentan as an active agent with a particle size distribution having a D90% less than 80 microns and D50% less than 30 microns.

In an embodiment of the present invention relates to a pharmaceutical composition comprising macitentan or pharmaceutically acceptable salt, solvates, hydrates or morphological forms thereof, prepared by a process comprising the following steps:
(d) combining macitentan with lactose;
(e) adding one or more other pharmaceutically acceptable excipients and;
(f) formulating into an oral solid dosage form.

The pharmaceutical composition of the present invention can include all the oral solid dosage forms known to a person skilled in art, viz. formulations such as single unit dosage form in the form of tablet, bilayer tablet, inlaid tablet, tablet in tablet, multilayered tablet, minitablet filled in capsule and the like; beads, pellets presented in a sachet, capsule or tablet, capsules such as soft and hard gelatin; lozenges or sachets; granulates, microparticles, multiparticulates, powder and the like.

According to the present invention tablets can be prepared either by direct compression, dry compression (slugging), or wet granulation. The granulating aid in the wet granulation method may comprise use of aqueous solvent such as water or an organic solvent such as water, ethanol, or a mixture thereof. Suitable solvents according to the present invention can be any solvent in which the binder is soluble or dispersible and is selected from, but not limited to, isopropyl alcohol, ethanol, water, acetone, methylene chloride and the like either alone or mixtures thereof.

In an embodiment of the present invention relates to a pharmaceutical composition of macitentan is a film coated tablet. The film coating composition comprises a film forming agent which provides smooth film-forming coating suspension/solution and enhance the rheological mechanical strength properties of film coating gel matrices. Film forming agents include, but not limited to, polyvinyl pyrrolidone, water soluble polymer, natural gum, starch, and cellulosic polymer. A water soluble polymer may include, but not limited to, polyvinyl alcohol (e.g. Opadry), partially hydrolyzed polyvinyl acetate, polyvinyl pyrrolidone, alkyl celluloses such as methylcellulose, ethylcellulose, propylcellulose and derivatives thereof. A cellulosic polymer may include a molecule comprising at least one cellulose polymer or derivative modified with small amount of propylene glycol ether group attached to the cellulose anhydroglucose chain affording binding properties that enhance the reinforcing film properties of film application. Example of cellulosic polymers include, but not limited to, hydroxypropyl methyl cellulose (“HPMC”), carboxymethyl cellulose (“CMC”) or salts thereof, hydroxypropyl cellulose (“HPC”), methylcellulose (“MC”), hydroxyethyl cellulose (“HEC”), and the like. In addition, cellulosic polymers may be characterized as ionic or non-ionic. Ionic cellulosic polymer includes, for example, sodium CMC. Non-ionic cellulosic polymers include, for example, HPMC, HPC, HEC, and MC. Varieties of commercially available cellulosic polymers exist and may include, for example, Spectracel® HPMC compositions (available from Sensient Technologies). Further, other commercially available coating materials are available and marketed under the brand name Opadry® for example Opadry II Gray which contains: lactose monohydrate NF, hypromellose type 2910 USP, titanium dioxide USP, triacetin USP, and iron oxide black JPE; Opadry II Pink which contains: hypromellose type 2910 USP, titanium dioxide USP, lactose monohydrate NF, polyethylene glycol 3350 NF, triacetin USP, and FD&C Red #40; Opadry II Blue which contains: hypromellose type 2910 USP, lactose monohydrate NF, FD&C Blue #1, polyethylene glycol 3350 NF, FD&C Blue #2, titanium dioxide USP, triacetin USP, and D&C Yellow #10; Opadry II Yellow which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, iron oxide yellow NF, polyethylene glycol 3350 NF, and triacetin USP; Opadry II Purple which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, D&C Red #27, polyethylene glycol 3350 NF, triacetin USP, and FD&C Blue #1 and the like.

In an embodiment, the composition of the present invention may additionally comprise of a colorant in order to produce a desirable color. Colors known to be 'FD&C’ certified may be used to provide coloring to the product and are within the purview of the present invention. Suitable colorants include natural colorants i.e., pigments and dyes obtained from mineral, plant, and animal sources. Examples of natural colorants include red ferric oxide, yellow ferric oxide, annattenes, alizarin, indigo, rutin, quercetin, and the like. Synthetic colorants may also be used, which is typically an FD&C or D&C dye, e.g., an approved dye selected from ‘coal-tar’ dyes, such as a nitroso dye, a nitro dye, an azo dye, an oxazine, a thiazine, a pyrazolone, a xanthene, an indigoid, an anthraquinone, an acridine, a rosaniline, a phthalein, a quinoline, or a ‘lake’ thereof, i.e. an aluminum or calcium salt thereof. Preferred colorants are food colorants in the 'GRAS' (Generally Regarded as Safe) category.

It is also desirable that the compositions of the present invention are chemically stable and protected from degradation either by oxidation, hydrolysis, isomerisation, photolysis, polymerization, or any other method of degradation. The degradation may be as a result of mixing with excipients or by any other method, could lead to a change in bioavailability and could also lead to toxicity. Chemical stability can be measured by a suitable, stability indicating chromatographic method for determining degradation products (see Aulton Me., Pharmaceutics - The Science of Dosage Form Design, 2.sup.nd Edition, 2002, Churchill Livingstone).

The composition of the present invention can be packed into suitable containers such as bottle, blister or pouch. Further, the package may optionally contain a desiccant or an antioxidant or oxygen absorbent or combination thereof.

In an embodiment, the composition of the present invention provides a method of treating pulmonary arterial hypertension comprising the administration to a patient in need thereof a pharmaceutical composition.

In an embodiment,the present invention provides a method of treating pulmonary arterial hypertension comprising the administration to a patient in need thereof a pharmaceutical composition comprising: (a) macitentan or pharmaceutically acceptable salt, solvates, hydrates or morphological forms thereof, (b) a filler consisting of lactose, (c) one or more disintegrant, (d) a surfactant, and (e) a lubricant.

In an embodiment,the present invention provides a method of using such composition indicated to treat pulmonary arterial hypertension (PAH, WHO Group I), and to delay disease progression.

The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1:
S. No Ingredients %w/w
Dry Mix
1 Macitentan 13.70
2 Lactose monohydrate 69.86
Binder solution
3 Hypromellose 4.12
4 Polyoxyethylene monostearate (Myrj 49) 0.68
5 Purified water q.s.
Extra granular
6 Pregelatinized starch 6.85
7 Magnesium stearate 0.68
Total (Core Tablet) 95.89
Film coating
8 Film coating [Polyvinyl alcohol, Soya lecithin, talc, titanium dioxide and xanthan gum] 4.11
Total (Coated Tablets) 100.00
q.s.: Quantity sufficient
Manufacturing process:
1. Macitentan and lactose monohydrate were sifted through ASTM Mesh No 40.
2. Binder solution was prepared by dissolving hypromellose and Polyoxyethylene monostearate in purified water.
3. Blend of step 1 was dry mixed in rapid mixer granulator for 10 minutes.
4. Blend of step 3 was granulated with the binder solution of step 2.
5. Granules were dried at the inlet of 60°C, until LOD reaches NMT 3.0%.
6. Granules were milled through quadro co-mill at medium speed and sift through ASTM Mesh No 20.
7. Pregelatinized starch was sifted through ASTM Mesh No 40 and blended with step 6 for 10 minutes in low shear blender.
8. Magnesium stearate was sifted through ASTM Mesh No 40 and blended with step 7 for 5 minutes in low shear blender.
9. Blend of step 8 was compressed with plain circular shaped toolings.
10. The tablet of step 9 was coated using 12% aqueous dispersion of the coating material up to the weight gain of 2-3%.

Example 2:
S. No Ingredients % w/w
1 Macitentan 13.70
2 Lactose monohydrate 69.86
Binder solution
3 Hypromellose 4.12
4 Sodium lauryl sulphate 0.68
5 Purified water q.s.
Extra granular
6 Croscarmellose sodium 6.85
7 Stearic acid 0.68
Total (Core Tablet) 95.89
Film coating
8 Film coating [Polyvinyl alcohol, Soya lecithin, talc, titanium dioxide and xanthan gum] 4.11
Total (Coated Tablets) 100.00
q.s.: Quantity sufficient
Manufacturing process:
1. Macitentan and lactose monohydrate were sifted through ASTM Mesh No 40.
2. Binder solution was prepared by dissolving hypromellose and sodium lauryl sulphate in purified water.
3. Blend of step 1 was dry mixed in rapid mixer granulator for 10 minutes.
4. Blend of step 3 was granulated with the binder solution of step 2.
5. Granuleswere dried at the inlet of 60°C, until LOD reaches NMT 3.0%.
6. Granules were milled through quadro co-mill at medium speed and sift through ASTM Mesh No 20.
7. Croscarmellose sodium was sifted through ASTM Mesh No 40 and blended with step 6 for 10 minutes in low shear blender.
8. Stearic acid was sifted through ASTM Mesh No 40 and blended with step 7 for 5 minutes in low shear blender.
9. Blend of step 8 was compressed with plain circular shaped toolings.
10. The tablet of step 9 was coated using 12% aqueous dispersion of the coating material up to the weight gain of 2-3%.

Example 3:
S. No Ingredients %w/w
1 Macitentan 13.70
2 Microcrystalline cellulose 31.14
3 Lactose monohydrate 38.73
Binder solution
4 Povidone 4.11
5 Polysorbate 0.68
6 Purified water q.s.
Extra granular
7 Pregelatized Starch 6.85
8 Magnesium stearate 0.68
Total (Core Tablet) 95.89
Film coating
9 Film coating [Polyvinyl alcohol, Soya lecithin, talc, titanium dioxide and xanthan gum] 4.11
Total (Coated Tablets) 100.00
q.s.: Quantity sufficient
Manufacturing process:
1. Macitentan, Microcrystalline cellulose and lactose monohydrate were sifted through ASTM Mesh No 40.
2. Binder solution was prepared by dissolving povidone and polysorbate in purified water.
3. Blend of step 1was dry mixed in rapid mixer granulator for 10 minutes.
4. Blend of step 3was granulated with the binder solution of step 2.
5. Granules were dried at the inlet of 60°C, until LOD reaches NMT 3.0%.
6. Granules were milled through quadro co-mill at medium speed and sift through ASTM Mesh No 20.
7. Pregelatinized starch was sifted through ASTM Mesh No 40 and blended with step 6 for 10 minutes in low shear blender.
8. Magnesium stearate was sifted through ASTM Mesh No 40 and blend with step 7 for 5 minutes in low shear blender.
9. Blend of step 8was compressed with plain circular shaped toolings.
10. The tablet of step 9 was coated using 12% aqueous dispersion of the coating material up to the weight gain of 2-3%.

Example 4:
S.No Ingredients % age w/w
1 Macitentan 13.70
2 Microcrystalline cellulose 69.86
Binder solution
3 Hypromellose 4.12
4 Polyoxyethylene monostearate (Myrj 49) 0.68
5 Purified water q.s.
Extra granular
6 Pregelatinized starch 6.85
7 Magnesium stearate 0.68
Total (Core Tablet) 95.89
Film coating
8 Film coating [Polyvinyl alcohol, Soya lecithin, talc, titanium dioxide and xanthan gum] 4.11
Total (Coated Tablets) 100.00
q.s.: Quantity sufficient
Manufacturing process:
1. Macitentan and microcrystalline cellulose were sifted through ASTM Mesh No 40.
2. Binder solution was prepared by dissolving hypromellose and Polyoxyethylene monostearate in purified water.
3. Blend of step 1was dry mixed in rapid mixer granulator for 10 minutes.
4. Blend of step 3was granulated with the binder solution of step 2.
5. Granules were dried at the inlet of 60°C, until LOD reaches NMT 3.0%.
6. Granules were milled through quadro co-mill at medium speed and sift through ASTM Mesh No 20.
7. Pregelatinized starch was sifted through ASTM Mesh No 40 and blended with step 6 for 10 minutes in low shear blender.
8. Magnesium stearate was sifted through ASTM Mesh No 40 and blend with step 7 for 5 minutes in low shear blender.
9. Blend of step 8was compressed with plain circular shaped toolings.
10. The tablet of step 9 was coated using 12% aqueous dispersion of the coating material up to the weight gain of 2-3%.

Examples 5 to 6:
S. No. Ingredients Example 5
%age (w/w) Example 6
%age (w/w)
Intra granular ingredients
1. Macitentan 13.70 13.70
2. Lactose Monohydrate 78.81 -
3. Microcrystalline Cellulose - 78.81
4. Povidone 1.88 1.88
5. Polysorbate 80 0.19 0.19
6. Sodium Starch Glycolate 1.02 1.02
Extra granular Ingredients
7. Sodium Starch Glycolate 1.02 1.02
8. Magnesium stearate 0.28 0.28
Film Coating
9. Opadry White 3.10 3.10
q.s.: Quantity sufficient
Manufacturing process:
1. Macitentan was sifted through a suitable screen.
2. LactoseMonohydrate and sodium starch glycolate were sifted separately through a suitable screen.
3. Macitentan and 20%Lactose Monohydrate or Microcrystalline Cellulose were co-sifted through a suitable screen.
4. The above material with remaining Lactose monohydrate or Microcrystalline Cellulose were co-sifted through suitable screen and re-sifted. Then the materials were loaded to high shear mixer.
5. The materials of step 4 were dry mixed in the high shear mixer with a predefined time.
6. The required quantity of Purified water was dispensed. Then Povidone and Polysorbate 80 were dissolved in it.
7. Granulation of the material of step 5 was carried outby using binder solution of step 6.
8. Wet mass of step 7 was dried to achieve a suitable LOD.
9. Granules of step 8 were sifted through suitable screen.
10. The retained granules were milled through multi mill / co-mill fitted with suitable screen and sifted the milled granules through suitable screen.
11. The extra-granular materials were sifted separately through suitable screen.
12. To the milled and sifted granules of steps 9 and 10, added Sodium Starch Glycolate from step 11 and carried out pre lubrication with a pre defined time.
13. Magnesium stearate from step 11 was added to the granules of step 12 and lubricatedfor a pre defined time.
14. The lubricated blend of step 13 was compressed with suitable punch.
15. Film coating of the tablets of step 14 were carried out with Opadry White.

Examples 7 to 8:
S. No. Ingredients Example 7
%age (w/w) Example 8
%age (w/w)
Intra granular ingredients
1. Macitentan 13.70 13.70
2. Lactose Monohydrate 63.23 63.23
3. Microcrystalline cellulose 11.58 11.58
4. Povidone 1.88 1.88
5. Sodium lauryl sulfate 1.19 -
6. Polyoxyethylene monostearate - 1.19
7. Sodium Starch Glycolate 1.92 1.92
Extra granular Ingredients
8. Sodium Starch Glycolate 1.92 1.92
9. Magnesium stearate 0.48 0.48
Film Coating
10. Opadry White 4.10 4.10
q.s.: Quantity sufficient
Manufacturing process:
1. Macitentan was sifted through a suitable screen.
2. Lactose Monohydrate, Sodium starch glycolate and Microcrystalline Cellulose were sifted separately through a suitable screen.
3. Macitentan and Microcrystalline Cellulose were co-sifted through a suitable screen.
4. The above material of step 3 was co-sifted with Lactose monohydrate through suitable screen and re-sifted. The materials were loaded to high shear mixer.
5. The materials of step 4 were dry mixed in the high shear mixer with a predefined time.
6. The required quantity of Purified water was dispensed. Then dissolve Povidone and Polyoxyethylene monostearate or Sodium Lauryl Sulfate were dissolved in it.
7. Granulation of the material of step 5was carried out by using binder solution of step 6.
8. The wet mass of step 7was dried to achieve a suitable LOD.
9. The granules of step 8 were sifted through suitable screen.
10. The retained granules were milled through multi mill / co-mill fitted with suitable screen and sifted the milled granules through suitable screen.
11. The extra-granular materials were sifted separately through suitable screen.
12. To the milled and sifted granules of steps 9 and 10, added Sodium Starch Glycolate from step 11 and carried out pre lubrication with a pre defined time.
13. Magnesium stearate from step 11 was addedto the granules of step 12 and lubricate for a pre defined time.
14. The lubricated blend of step 13 was compressed with suitable punch.
15. Film coating of the tablets of step 14 were carried out with Opadry White.

Examples 9 to 10:
S. No. Ingredients Example 9
%age (w/w) Example 10
%age (w/w)
Intra granular ingredients
1. Macitentan 13.70 13.70
2. Lactose Monohydrate 48.23 48.23
3. Microcrystalline cellulose 30.58 30.58
4. Povidone 2.38 2.38
5. Polysorbate 80 0.69 0.69
6. Croscarmellose sodium 0.24 -
7. Crospovidone - 0.24
Extra granular Ingredients
8. Croscarmellose sodium 0.24 -
9. Crospovidone - 0.24
10. Magnesium stearate 0.48 0.48
Film Coating
11. Opadry White 3.46 3.46
q.s.: Quantity sufficient

Manufacturing process:
1. Macitentan was sifted through a suitable screen.
2. Lactose Monohydrate, Microcrystalline Cellulose and Croscarmellose sodium or Crospovidone were sifted through a suitable screen.
3. Macitentan and Microcrystalline Cellulose were co-sifted through a suitable screen.
4. The above materials with Lactose monohydrate and Croscarmellose sodium or Crospovidone were firstly co-sifted and then re-sifted. The materials were loaded to high shear mixer.
5. The materials of step 4 were dry mixed in the high shear mixer with a predefined time.
6. Dispense therequired quantity of Purified water was dispensed. Then Povidone and Polysorbate 80 were dissolved in it.
7. Granulation of the material of step 5 was carried out by using binder solution of step 6.
8. The wet mass of step 7 was dried to achieve a suitable LOD.
9. The granules of step 8 were sifted through suitable screen.
10. The retained granules were milled through multi mill / co-mill fitted with suitable screen and sifted the milled granules through suitable screen.
11. The extra-granular materials were sifted separately through suitable screen.
12. To the milled and sifted granules steps 9 and 10, added Croscarmellose sodium or Crospovidone from step 11 and carried out pre lubrication with a pre defined time.
13. Magnesium stearate from step 11 was added to the granules of step 12 and lubricated with a pre defined time.
14. The lubricated blend of step 13 was compressed with suitable punch.
15. Film coating of the tablets of step 14 were carried out with Opadry White.

Examples 11 to 12:
S. No. Ingredients Example 11
%age (w/w) Example 12
%age (w/w)
Intra granular ingredients
1. Macitentan 13.70 13.7
2. Lactose Monohydrate 49.23 49.23
3. Microcrystalline cellulose 25.58 25.58
4. Sodium Starch Glycolate 2.01 2.01
5. Hydroxypropyl methylcellulose (HPMC) 3.12 -
6. Pregelatinised Starch - 3.12
7. Polysorbate 80 0.39 0.39
Extra granular Ingredients
8. Sodium Starch Glycolate 2.01 2.01
9. Stearic Acid 0.54 -
10. Sodium Stearyl Fumarate (SSF) - 0.54
Film Coating
11. Opadry White 3.42 3.42
q.s.: Quantity sufficient
Manufacturing process:
1. Macitentan was sifted through a suitable screen.
2. Lactose Monohydrate, Microcrystalline Cellulose, HPMC / Pregelatinised Starch and Sodium starch glycolate were sifted separately through a suitable screen.
3. Macitentan and Microcrystalline Cellulose were co-sifted through a suitable screen.
4. The above material with Lactose monohydrate, HPMC or Pregelatinised Starch and Sodium starch glycolate were co-sifted through suitable screen and then re-sifted. The materials were loaded to high shear mixer.
5. The materials of step 4 were dry mixed in the high shear mixer with a predefined time.
6. Dispense therequired quantity of Purified water was dispensed. Then Polysorbate 80 was dissolved in it.
7. Granulation of the material of step 5 was carried out by using binder solution of step 6.
8. The wet mass of step 7 was dried to achieve a suitable LOD.
9. The granules of step 8 were sifted through suitable screen.
10. The retained granules were milled through multi mill / co-mill fitted with suitable screen and sifted the milled granules through suitable screen.
11. The extra-granular materials were sifted separately through suitable screen.
12. To the milled and sifted granules of steps 9 and 10, added Sodium Starch Glycolate from step 11 and carried out pre lubrication with a pre defined time.
13. Stearic Acid / SSF (extra-granular materials) from step 11 was added to the granules of step 12 and lubricated with a pre defined time.
14. The lubricated blend of step 13 was compressed with suitable punch.
15. Film coating of the tablets of step 14 were carried out with Opadry White.
Example 13:
S. No. Ingredients %age (w/w)
Intra granular ingredients
1. Macitentan 13.70
2. Lactose Monohydrate 31.23
3. Microcrystalline cellulose 46.45
4. Sodium Starch Glycolate 3.44
5. Polysorbate 80 0.29
Extra granular Ingredients
6. Magnesium stearate 0.78
Film Coating
7. Opadry White 4.11
q.s.: Quantity sufficient
Manufacturing process (Direct Compression):
1. Macitentan was sifted through a suitable screen.
2. Polysorbate 80, Lactose Monohydrate, Microcrystalline Cellulose and Sodium starch glycolate were sifted separately through a suitable screen.
3. Macitentan, Polysorbate 80 and 20% Lactose Monohydrate was co-sifted through a suitable screen.
4. The above material of step 3 were co-sifted with remaining Lactose monohydrate, Microcrystalline Cellulose and Sodium Starch Glycolate through suitable screen and then re-sifted. Load the materials to Blender and mix for a predetermined time period.
5. Magnesium stearate was sifted separately through suitable screen and lubricatedthe blend of step 4 for a pre defined time.
6. The lubricated blend of step 5 was compressed with suitable punch.
7. Film coating of the tablets of step 6 were carried out with Opadry White.

Manufacturing process (Compaction):
1. Macitentan was sifted through a suitable screen.
2. Polysorbate 80, LactoseMonohydrate, Microcrystalline Cellulose and Sodium starch glycolate were sifted separately through a suitable screen.
3. Macitentan, Polysorbate 80 and 20%Lactose Monohydrate was co-sifted through a suitable screen.
4. The above material of step 3 was co-sifted with remaining Lactose monohydrate, microcrystalline cellulose and Sodium starch glycolate through suitable screen and then re-sifted. The materials were loaded to blender and mixed for a predetermined time period.
5. Compaction of the mixed mass of step 4 was carried out with suitable roller and feeder speed.
6. The granules of step 6 were sifted through suitable screen.
7. The retained granules were milled through multi mill / co-mill fitted with suitable screen and sifted the milled granules through suitable screen.
8. Magnesium stearate was sifted separately through suitable screen and lubricatedthe blend of step 7 with a pre defined time.
9. The lubricated blend of step 8 was compressed with suitable punch.
10. Film coating of the tablets of step 9 were carried out with Opadry White.

Manufacturing process (Top Spray Granulation):
1. Macitentan was sifted through a suitable screen.
2. LactoseMonohydrate, Microcrystalline Cellulose and Sodium starch glycolate were sifted separately through a suitable screen.
3. Macitentan and 20%Lactose Monohydrate were co-sifted through a suitable screen.
4. The above material of step 3 was co-sifted with remaining Lactose monohydrate, Microcrystalline Cellulose and Sodium starch glycolate through suitable screen and then re-sifted.
5. The materials of step 4 were loaded to the Fluid Bed Processor.
6. The required quantity of Purified water was dispensed. Then Polysorbate 80 was dissolved in it.
7. Granulation of material of step 5 was carried out by using binder solution of step 6.
8. The wet mass of step 7 was dried to achieve a suitable LOD.
9. The granules of step 8 were sifted through suitable screen.
10. The retained granules were milled through multi mill / co-mill fitted with suitable screen and sifted the milled granules through suitable screen.
11. Magnesium stearate was sifted separately through suitable screen and lubricated the granules of step 10 with a pre defined time.
12. The lubricated blend of step 12 was compressed with suitable punch.
13. Film coating of the tablets of step 13 were carried out with Opadry White. ,CLAIMS:We Claim:

1. A pharmaceutical composition comprising: (a) macitentan or pharmaceutically acceptable salt, solvates, hydrates or morphological forms thereof, (b) a filler consisting of lactose, (c) one or more disintegrant, (d) a surfactant, and (e) a lubricant.

2. The pharmaceutical composition according to claim 1, which is an oral solid dosage form.

3. The pharmaceutical composition according to claim 1, wherein the disintegrant is selected from sodium starch glycolate, cellulose and its derivatives including low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, ion-exchange resins, starch and modified starch including pregelatinized starch, formalin-casein and combinations thereof.

4. The pharmaceutical composition according to claim 1, wherein the surfactant is selected from polysorbates, sodium lauryl sulphate, polyethylene polyoxypropylene polymers, polyoxylethylene stearates, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene C1-4 alkyl ethers, sucrose monoesters, lanolin esters, ethers and combination thereof.

5. The pharmaceutical composition according to claim 1, wherein the lubricant is selected from sodium stearyl fumarate, calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, stearic acid, talc, vegetable oil, zinc stearate and combination thereof.

6. The pharmaceutical composition according to claim 1, wherein the macitentan is crystalline form I.

7. The pharmaceutical composition according to claim 1, wherein the macitentan is a free base with a particle size distribution having a D90% less than 200 microns and D50% less than 150 microns.

8. A pharmaceutical composition comprising macitentan or pharmaceutically acceptable salt, solvates, hydrates or morphological forms thereof, prepared by a process comprising the following steps:
(g) combiningmacitentan with lactose;
(h) adding one or more other pharmaceutically acceptable excipients and;
(i) formulating into an oral solid dosage form.

9. A pharmaceutical composition comprising: (a) macitentan or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof, (b) a filler consisting of lactose, in a total amount of 10% to 98% by weight of the composition, (c) one or more disintegrant, in a total amount of 0.5% to 20% by weight of the composition, (d) a surfactant, in a total amount of 0.1% to 5% by weight of the composition, and (e) a lubricant.

10. The pharmaceutical composition according to claim 1 which is useful for treating pulmonary arterial hypertension.