A FILM COATED TABLET COMPRISING SELEXIPAG

Field of the Invention

The present invention relates to a film coated tablet comprising selexipag or crystalline polymorph thereof and D-mannitol as a filler, one more filler and crospovidone as disintegrant. Furthermore, the tablet is obtained using an effective process.

Background of the Invention

Selexipag is prostacyclin receptor agonist that causes vasodilation in pulmonary vasculature and is used in the therapy of pulmonary arterial hypertension (PAH). Selexipag also known as 2-(4-((5,6- diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)-N-(methylsulfo nyl)acetamide can be represented by the following chemical structure according to Formula I:

Formula I: Selexipag

Depending on the dose strength, each round film-coated tablet for oral administration contains 200, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg of Selexipag. The Uptravi® film-coated tablet is a standard immediate-release tablet that contains D-mannitol, corn starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose and magnesium stearate. The tablets are film coated with a coating material containing hypromellose, propylene glycol, titanium dioxide, carnauba wax along with mixtures of iron oxide red, iron oxide yellow or iron oxide black.

Selexipag is considered to be a BCS (Biopharmaceutics Classification System) Class II drug, i.e. having high permeability and low solubility.

Also, some of solid state forms tend to convert to other forms during storage and manufacturing process thereby leading to incorrect dosing.

EP3481807 (Al) discloses novel crystalline forms of selexipag and its process for the preparation thereof. WO 2017/029594 describes the preparation of amorphous selexipag by dissolving the drug in a suitable solvent, e.g. acetone, and removing the solvent by, e.g., evaporation, spray-drying or freeze- drying.

In prior art, there are also several patents which disclose selexipag in oral pharmaceutical dosage forms. However, despite the dissolution problem of selexipag, an effective formulation and method has not been disclosed.

There still remains a need in the art to provide an improved a film coated tablet comprising selexipag or crystalline polymorph thereof having high solubility, excellent physicochemical properties and accordingly a high bioavailability and a long-term stability.

Detailed Description of the Invention

The main object of the present invention is to provide a film coated tablet comprising selexipag or crystalline polymorph thereof with having desired level of dissolution rate and high stability and excellent physicochemical properties, such as flowability, compressibility and content uniformity which overcomes the above-described problems in the prior art and have additive advantages over them.

Another object of the present invention is to provides a process for a film coated tablet composition comprising selexipag or crystalline polymorph thereof. The process is a simple, rapid, cost effective, time-saving and industrially convenient method.

Like the other poorly soluble in water molecules, low solubility of selexipag results in low dissolution. Also, selexipag or crystalline polymorph thereof is used small proportion that can lead to considerable problems during the manufacture of the composition with regard to the uniformity of the content of active agent in the individual composition units. Because of problems uniformity of the content, the active substance may interact with several excipients. It reflects that content uniformity make an important role in the dissolution of the drug.

In this invention, we found that crospovidone has proven to offer substantial advantages as disintegrant because of its ability to turn low-soluble selexipag into fast-dissolving stable tablets. Also, its use in the specified range provided the desired dissolution profile. According to one embodiment of the present invention, a film coated tablet comprises

Selexipag or crystalline polymorph thereof

D-mannitol as a filler and one more filler

Crospovidone as a disintegrant, wherein the amount of crospovidone is between 2.0% and 10.0% by weight of the total tablet.

According to one embodiment of this invention, the amount of selexipag or crystalline polymorph thereof is between 0.05% and 5.0%, preferably between 0.05% and 2.0% by weight of the total tablet.

According to one embodiment of this invention, selexipag is present in the form of amorph or form P or form 3 or form 1 or mixtures thereof.

According to one embodiment of this invention, selexipag is present in the form of amorph.

According to one embodiment of this invention, selexipag is present in the form of form P. It provides a tablet with high yields and purity.

According to one embodiment of this invention, selexipag is present in the form of form 3.

According to one embodiment of this invention, the amount of crospovidone is between 3.0% and 8.0% by weight of the total tablet.

According to one embodiment of this invention, the amount of D-mannitol is between 45.0% and 58.0%, between 50.0% and 56.0% by weight of the total tablet.

Suitable fillers are selected from the group comprising corn starch, microcrystalline cellulose, lactose monohydrate, cellulose, cellulose acetate, compressible sugar, ethylcellulose, lactitol, lactose, magnesium oxide, maltodextrin, maltose, sorbitol, sucrose, talc, or mixtures thereof.

According to one embodiment of the present invention, besides D-mannitol, another filler is corn starch. Using D-mannitol and corn starch provides both the desired stability and excellent physicochemical properties.

According to one embodiment of this invention, the amount of filler is between 70.0% and 95.0%, between 78.0% and 90.0% by weight of the total tablet.

According to one embodiment of this invention, the amount of corn starch is between 25.0% and 45.0%, between 30.0% and 40.0% by weight of the total tablet. According to one embodiment of the present invention, the film coated tablet comprises at least one pharmaceutically acceptable excipient selected from the group comprising binders, lubricants or mixtures thereof.

Suitable binders are selected from the group comprising hydroxypropyl methyl cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyethylene glycol, starch, pregelatinized starch, sodium alginate, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, polymethacrylates, methacrylate polymers, polysaccharides, carbomer, poloxamer, polydextrose, polyethylene oxide or mixtures thereof.

According to one embodiment of the present invention, the binder is hydroxypropyl methyl cellulose. The use of HPMC while preparing the solution in which selexipag dissolves provided the pH range required for the dissolution of selexipag. This pH range is between 5 and 8.

According to one embodiment of this invention, the amount of binder is between 1.0% and 8.0%, between 2.0% and 6.0% by weight of the total tablet.

Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, sodium stearyl fumarate, potassium stearate, stearic acid, sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols or mixtures thereof.

According to one embodiment of the present invention, the lubricant is magnesium stearate.

According to one embodiment of this invention, the amount of lubricant is between 0.5% and 3.5% by weight of the total tablet.

According to one embodiment of the present invention, the film coated tablet further comprises at least one coloring agent.

Suitable coloring agents are selected from the group comprising indigo carmin aluminium lake, ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof. Coloring agent contributes positively to the shelf life of the product and so the desired stability. According to one embodiment of this invention, the film coated tablet comprises;

Crystalline form-P, 1 or 3 or amorph of selexipag D-Mannitol Corn starch 2.0-10.0% by weight of crospovidone Hydroxypropyl methyl Cellulose E3 LV Magnesium stearate.

According to one embodiment of this invention, the film coated tablet comprises;

Crystalline form-P or 3 or amorph of selexipag

D-Mannitol

Corn starch

2.0-10.0% by weight of crospovidone

Hydroxypropyl methyl Cellulose E3 LV

Magnesium stearate

Coloring agent.

According to one embodiment of this invention, the film coated tablet is obtained by wet granulation using solvent.

Suitable solvents are selected from the group comprising pure water, dichloromethane, 0.1N HCI, methanol, ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, glycerine, cyclomethicone, glycerine triacetate, diethylene glycol monoethyl ether or mixtures thereof. Preferably, the solvent is water or dichloromethane or methanol or ethanol .

According to one embodiment of this invention, a process for preparing a film coated tablet comprising selexipag or crystalline polymorph thereof comprises the following steps: a) Dissolving a binder in solvent and adjusting pH at the solution in the range of 5-8, b) Mixing selexipag or crystalline polymorph thereof and a half of crospovidone, and then adding another half of crospovidone and mixing again, c) Adding % of a filler and mixing, then adding the remaining part of a filler and mixing again, d) Adding a half of D-mannitol and mixing, and then adding another half of D-mannitol and mixing,

This geometric dilution method provides the homogeneity and content uniformity of the active substance used in low amounts and the desired dissolution profile. In this invention, to eliminate this problem, wet granulation with geometric dilution method is preferred in terms of pharmacotechnical properties, such as flowability, compressibility and content uniformity of selexipag. Especially, using suitable solvent also provides the desired stability.

According to one embodiment of this invention, a process for preparing a film coated tablet comprising selexipag or crystalline polymorph thereof comprises the following steps: a) Dissolving a binder in solvent and adjusting pH at the solution in the range of 5-8, b) Mixing selexipag or crystalline polymorph thereof and a half of crospovidone, and then adding another half of crospovidone and mixing again, c) Adding % of corn starch and mixing, then adding the remaining part of corn starch and mixing again, d) Adding a half of D-mannitol and mixing and then adding another half of D-mannitol and mixing, e) Granulating the dry mixture at step (d) with the solution step (a) and obtained wet granules, f) Drying the wet granules and then sieving, g) Adding at least one lubricant and then mixing, h) Compressing the mixture into tablets, i) Coating the tablets.

According to one embodiment of this invention, a process for preparing a film coated tablet comprising selexipag or crystalline polymorph thereof comprises the following steps: a) Dissolving a binder in solvent and adjusting pH at the solution in the range of 5-8, b) Mixing selexipag or crystalline polymorph thereof and a half of crospovidone, and then adding another half of crospovidone and mixing again, c) Adding % of corn starch and mixing, then adding the remaining part of corn starch and mixing again, d) Adding a half of D-mannitol and mixing and then adding another half of D-mannitol and mixing, e) Granulating the dry mixture at step (d) with the solution step (a) and obtained wet granules, f) Drying the wet granules and then sieving, g) Adding coloring agent and mixing, h) Adding at least one lubricant and then mixing, i) Compressing the mixture into tablets, j) Coating the tablets. Example 1:

Example 2: A process for example 1 or 2; a) Dissolving a binder in water and adjusting pH at the solution in the range of 5-8, b) Mixing selexipag or crystalline polymorph thereof and a half of crospovidone, and then adding another half of crospovidone and mixing again, c) Adding % of corn starch and mixing, then adding the remaining part of corn starch and mixing again, d) Adding a half of D-mannitol and mixing and then adding another half of D-mannitol and mixing, e) Granulating the dry mixture at step (d) with the solution step (a) and obtained wet granules, f) Drying the wet granules and then sieving, g) Adding at least one lubricant and then mixing, h) Compressing the mixture into tablets, i) Coating the tablets.

Example 3:

A process for example 3; a) Dissolving a binder in water and adjusting pH at the solution in the range of 5-8, b) Mixing selexipag or crystalline polymorph thereof and a half of crospovidone, and then adding another half of crospovidone and mixing again, c) Adding % of corn starch and mixing, then adding the remaining part of corn starch and mixing again, d) Adding a half of D-mannitol and mixing and then adding another half of D-mannitol and mixing, e) Granulating the dry mixture at step (d) with the solution step (a) and obtained wet granules, f) Drying the wet granules and then sieving, g) Adding coloring agent and mixing, h) Adding at least one lubricant and then mixing, i) Compressing the mixture into tablets, j) Coating the tablets.