Field of the Invention

The present invention relates to a capsule formulation comprising macitentan free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters and at least one pharmaceutically acceptable excipient.

Background of the Invention

Pulmonary arterial hypertension (PAH) is a disease that accumulates pulmonary artery endothelial cells, muscle layer and adventitia, which restricts pulmonary artery blood flow, which leads to increased pulmonary vascular resistance, progressive increase in pulmonary artery pressure, and finally causes the right heart A malignant cardiovascular disease of failure or even death. Its main feature is the gradual increase in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) caused by pulmonary artery obstruction, accompanied by irreversible pulmonary vascular remodeling. Patients with severe symptoms can cause right heart failure and death, with poor prognosis and high mortality.

Macitentan is an endothelin receptor antagonist, which prevents endothelin (ET-1) from binding to ETA and ETB receptors, and exhibits high affinity and sustained occupancy in human pulmonary artery smooth muscle cells.

The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2- pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide and its chemical structure is shown in the Formula 1.

Formula I: Macitentan

Macitentan is the active ingredient marketed under the brand OPSUMIT® for the long-term treatment of pulmonary arterial hypertension. Macitentan is a BCS class II drug substance characterized by low solubility and high permeability. The poor solubility and low dissolution rate of poorly water-soluble drugs in the aqueous gastrointestinal fluids often cause insufficient bioavailability. It is known that for BCS class II drugs rate limiting step is drug release from the dosage form and solubility in the gastric fluid and not the absorption, so increasing the solubility in turn increases the bioavailability for BCS class II drugs.

W02007031933 application discloses solid oral pharmaceutical compositions of macitentan comprising silicon dioxide or other incompatible excipients.

WO2014173805 application discloses macitentan compositions comprising a specific polymorphic form. In particular, the document discloses the preparation of a pharmaceutical composition comprising crystalline macitentan free base.

WO 2018153925 application discloses macitentan compositions which does not contain surfactants.

Stability-related problems do occur in macitentan under the influence of ambient and physical conditions. Especially, macitentan is reactive against the excipients employed in developing formulations containing the same. This fact causes impurities to occur in the formulation and leads to the inclusion of undesired components into the formulation.

Accordingly, there is still a need for stable solid pharmaceutical formulations eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.

Consequently, it is clear that there is no teaching, suggestion or motivation in the prior art about how to develop a stable capsule formulation enabling a simple manufacturing process and ensuring the release of the active agent at the specified site of delivery at the same time.

Detailed Description of the Invention

The main object of the present invention is to provide a capsule formulation comprising macitentan which is an easily applicable product, eliminating all problems and bringing additional advantages to the relevant prior art.

Another object of the present invention is to provide a capsule formulation comprising macitentan which has the desired stability, a short disintegration time, desired dissolution properties and enables a high bioavailability of macitentan in a patient. The capsule form has advantages over other known forms. For examples; capsules tend to break down more quickly than tablets, they may offer faster relief from symptoms than tablets, capsules are less likely to have an unpleasant taste or odor. It protects the sensitive active ingredient. In addition to all of these, capsule form also increases patient compliance.

The term “macitentan” as used herein refers to macitentan in the form the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixture thereof.

We found that macitentan has incompatibility problem and stability problem when it is combined with silicone dioxide. By keeping this excipient away from our formulation, we prevented macitentan from having a stability problem besides its dissolution disadvantage.

According to this embodiment of the present invention, a capsule formulation comprises macitentan free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters and at least one pharmaceutically acceptable excipient wherein is free of silicon dioxide. So, this formulation does not cause any stability problems. The capsule use in the treatment of pulmonary arterial hypertension.

According to this embodiment of the present invention, the capsule formulation comprises macitentan in an amount of between 0.1 mg to 300 mg.

According to this embodiment of the present invention, the capsule formulation comprises macitentan in an amount of between 0.1 mg to 100 mg.

According to this embodiment of the present invention, the amount of macitentan is between 0.1% to 50.0% by weight of the total formulation.

According to this embodiment of the present invention, the amount of macitentan is between 0.1% to 30.0% by weight or between 0.5% to 20.0% by weight of the total formulation.

An embodiment of this present invention, the capsule formulation comprises at least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, dispersing agents, surfactant, modified release agents, lubricants, glidants or mixtures thereof.

Suitable fillers are selected from group comprising lactose monohydrate, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, mannitol, ammonium alginate, calcium carbonate, anhydrous lactose, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, fructose, glyceryl palmitostearate, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar sphericals, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose, xylitol or mixtures thereof.

According to this embodiment of the present invention, the filler is lactose monohydrate, microcrystalline cellulose, mannitol, lactose, pregelatinized starch or mixtures thereof. Selected the filler provides the desired dissolution profile.

According to this embodiment of the present invention, the filler is lactose monohydrate.

According to this embodiment of the present invention, the filler is microcrystalline cellulose.

According to this embodiment of the present invention, the filler is mannitol.

According to this embodiment of the present invention, the filler is lactose.

According to this embodiment of the present invention, the filler is pregelatinized starch.

According to this embodiment of the present invention, the amount of filler is between 20.0% to 90.0% by weight of the total formulation.

According to this embodiment of the present invention, the amount of filler is between 35.0% to 85.0% by weight, preferably between 40.0 to 80.0% by weight of the total formulation.

Suitable binders are selected from the group comprising polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, sugars, cellulose acetate phthalate, chitosan, corn starch, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, polydextrose, polyethylene oxide, polymethacrylates, aluminum hydroxide, stearic acid, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.

According to this embodiment of the present invention, the binder is polyvinylpyrrolidone, hydroxypropyl methylcellulose or mixtures thereof.

According to this embodiment of the present invention, the amount of binder is between 0.1% to 25.0% by weight of the total formulation.

According to this embodiment of the present invention, the amount of binder is between 0.1% to 20.0% by weight, preferably between 1.0% to 15.0% by weight of the total formulation. Suitable disintegrants are selected from the group comprising crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, sodium starch glycolate, magnesium aluminium silica, sodium glycine carbonate or mixtures thereof.

According to this embodiment of the present invention, the amount of disintegrants is between 0.1% to 25.0% by weight of the total formulation.

According to this embodiment of the present invention, the amount of disintegrants is between 1.0% to 15.0% by weight, preferably between 1.0% to 10.0% by weight of the total formulation.

Suitable dispersing agents are selected from the group comprising calcium silicate, magnesium aluminum silicate, sorbitan esters, aluminum oxide, phospholipids, poloxamer or mixtures thereof.

Suitable surfactants are selected from the group comprising polysorbates, sodium lauryl sulphate, benzalconium chloride, docusate sodium, glyceryl esters, glyceryl monoleate, poloxamer, polyethylene alkyl ethers, polyglyceryl esters, polyoxyetylene esters, polyoxyetylene stearates, sodium stearate, hexadecyl pyridinium chloride or mixtures thereof.

Modified release formulations can be preferred. Modified release formulations are selected from the group comprising controlled release, sustained release, delayed release, extended release, repeat action system or mixtures thereof.

Suitable modified release agents are selected from the group comprising ethyl acrylate, polymethacrylates ( Eudragit ), ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxymethyl cellulose, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, polygalacturonic acid, chondroitic sulfate, xanthan gum, galactomannan, glucomannan, glyceryl behenate, nitrocellulose, methylcellulose, proteoglycan, glycerol, propylene glycol, macrogols, dibutyl sebacetate, citrate esters, triacetin, castor oil, acetylated monoglycerides, stearic acid, cetyl alcohol, cetostearyl alcohol, gelucire (stearyl macrogolglyceride) or a mixtures thereof. Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, talc, sodium chlorate, magnesium lauryl sulfate, sodium acetate, sodium benzoate, polyethylene glycol, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.

Suitable glidants are selected from the group comprising talc, aluminium silicate, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof.

According to this embodiment of the present invention, the amount of glidants is between 0.5% to 5.0% by weight of the total formulation. This ratio provides good flowability and content uniformity in the formulation.

According to this embodiment of the present invention, the capsule formulation comprising macitentan is in the form of enteric coated capsules which are capsules that have an acid resistant coating to prevent them from dissolving when they pass through the stomach. The enteric capsules are activated only when they pass through an alkaline environment that is with a pH factor of 5.5 or higher which is usually when they reach the small intestine.

According to this embodiment of the present invention, capsule comprises of different type of particles are selected from the group comprising mini-capsules, mini-tablets, pellets, granules, powders or mixtures thereof.

The term “pellets” refers to small particles with approximately uniform shapes and sizes produced by an extrusion process. A “small particle” refers to a particle of which diameter, length, height, and width is at most 10 mm (e.g., at most 2, 3, 4, 5, 6, 7, 8, or 9 mm).

The term “mini tablet”, as used herein, refers to small tablets with a diameter equal to or less than 4 mm that are typically filled into a capsule or further compressed into larger tablets. Thickness of this mini tablets equal to or less than 3 mm. The mini tablets have round shape and smooth surface to ease coating process.

According to this embodiment of the present invention, the form of formulation is minicapsule in capsule wherein the mini capsule comprises at least one active agent. Minicapsules is located within a capsule.

According to this embodiment of the present invention, the form of formulation is mini-tablets in capsule wherein a mini-tablet comprises at least one active agent. Mini-tablets is located within a capsule. According to this embodiment of the present invention, the form of formulation is pellet in capsule wherein pellet comprises at least one active agent. Pellet is located within a capsule.

According to this embodiment of the present invention, the form of formulation is powder in capsule. Powder is located within a capsule.

The capsule formulation of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.

According to this embodiment of the present invention, the capsule formulation are produced by wet granulation or dry granulation process therefore, a simple and low-cost production method was employed.

During wet granulation, solvents are used in the process. The solvent is selected from the group comprising water, acetone, ethanol, isopropanol or mixtures thereof.

According to this embodiment of the present invention, the capsule formulation comprises;

-the amount of macitentan is between 3.0% to 50.0% by weight,

- the amount of filler is between 20.0% to 90.0% by weight,

- the amount of binder is between 0.1% to 25.0% by weight of the total formulation.

According to this embodiment of the present invention, the capsule formulation comprises;

-the amount of macitentan is between 7.0% to 30.0% by weight,

- the amount of filler is between 35.0% to 85.0% by weight of the total formulation.

According to this embodiment of the present invention, the capsule formulation comprises;

-the amount of macitentan is between 7.0% to 30.0% by weight,

- the amount of glidants is between 0.5% to 5.0% by weight of the total formulation. Example 1 : A capsule formulation comprising macitentan Example 2: A capsule formulation comprising macitentan Example 3: A capsule formulation comprising macitentan