A film coated tablet comprising selexipag processed with wet granulation

Abstract

The present invention relates to a film coated tablet comprising selexipag or crystalline polymorph thereof and at least one pharmaceutically acceptable excipient, wherein the tablet is obtained by wet granulation with geometric dilution method.

Description

[0001] DESCRIPTION

[0002] A FILM COATED TABLET COMPRISING SELEXiPAG PROCESSED WITH WET GRANULATION

[0003] Field of the Invention

[0004] The present invention relates to a film coated tablet comprising selexipag or crystalline polymorph thereof and at least one pharmaceutically acceptable excipient, wherein the tablet is obtained by wet granulation with geometric dilution method.

[0005] Background of the Invention

[0006] 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-(methylsulfonyl)acetamide can be represented by the following chemical structure according to Formula I:

[0007] Formula I: Selexipag

[0008] 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.

[0009] Selexipag is considered to be a BCS (Biopharmaceutics Classification System) Class II drug, i.e. having high permeability and low solubility.

[0010] EP3481807 (Al) discloses novel crystalline forms of selexipag and its process for the preparation thereof.

[0011] 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. EP3705115 (Al) discloses a solid unit dosage form for oral administration (tablet or granules) containing non-crystalline selexipag in a polymeric matrix and mannitol. The solid dispersion is prepared by hot-melt extrusion, whereby the milled extrudate is subsequently subjected to a drygranulation process.

[0012] 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.

[0013] 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.

[0014] Detailed Description of the Invention

[0015] The main object of the present invention is to provide a film coated tablet comprises or crystalline polymorph thereof with having the desired level of dissolution rate and high stability and excellent physicochemical properties, such as flowability, compressibility, homogeneity, and content uniformity which overcomes the above-described problems in the prior art and have additive advantages over them.

[0016] Another object of the present invention is to provide a process for preparing 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. Preferably, the process is wet granulation with geometric dilution method.

[0017] 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.

[0018] According to one embodiment of this invention, a film coated tablet comprises selexipag or crystalline polymorph thereof and at least one filler wherein the tablet is obtained by wet granulation with geometric dilution method. Selexipag or crystalline polymorph thereof presents in low amount in the tablet. Thanks to using wet granulation with geometric dilution method, at the present invention, the film coated tablet which has a low amount of selexipag or crystalline polymorph thereof has been developed with excellent physicochemical properties. Also, this provides the desired stability and dissolution profile of the tablet.

[0019] This geometric dilution method provides the homogeneity and content uniformity of the active substance used in low amounts and the desired dissolution profile.

[0020] In this invention, to eliminate this problem, wet granulation with geometric dilution method is preferred in terms of physicochemical properties, such as flowability, compressibility and content uniformity of selexipag. Using suitable solvent also provides the desired stability.

[0021] 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 or isopropyl alcohol or mixtures thereof.

[0022] According to one embodiment of this invention, the use of the filler at the described amount helps to provide the uniformity of the content and so the desired dissolution profile.

[0023] Suitable fillers are selected from the group comprising corn starch, D-mannitol, microcrystalline cellulose, lactose monohydrate, cellulose, cellulose acetate, compressible sugar, ethylcellulose, lactitol, lactose, magnesium oxide, maltodextrin, maltose, sorbitol, sucrose, talc, or mixtures thereof.

[0024] According to one embodiment of the present invention, fillers are D-mannitol and corn starch. Using D-mannitol and corn starch together helps to provide both the desired stability and excellent physicochemical properties.

[0025] According to one embodiment of this invention, the amount of filler is between 78.0% and 90.0% by weight of the total tablet.

[0026] 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 and the amount of D-mannitol is between 45.0% and 58.0%, between 48.0% and 56.0% 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.

[0027] 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.

[0028] According to one embodiment of this invention, selexipag is present in the form of amorph.

[0029] 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.

[0030] According to one embodiment of this invention, selexipag is present in the form of form 3.

[0031] According to one embodiment of the present invention, the film coated tablet further comprises at least one pharmaceutically acceptable excipient selected from the group comprising disintegrants, binders, lubricants or mixtures thereof.

[0032] Suitable disintegrants are selected from the group comprising low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxymethyl starch or mixtures thereof.

[0033] According to one embodiment of this invention, the disintegrant is low-substituted hydroxypropyl cellulose. In this invention, we found that low-substituted hydroxypropyl cellulose 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.

[0034] According to one embodiment of this invention, the amount of low-substituted hydroxypropyl cellulose is between 2.0% and 10.0% by weight of the total tablet.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] According to one embodiment of the present invention, the lubricant is magnesium stearate.

[0039] According to one embodiment of this invention, the amount of lubricant is between 0.5% and 3.5% by weight of the total tablet.

[0040] According to one embodiment of the present invention, the film coated tablet further comprises at least one coloring agent.

[0041] Suitable coloring agents are selected from the group comprising indigo carmin aluminum 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. Due to their nature, coloring agents show antioxidant properties and often prevent the active substance from being oxidized. It also provides photostability by preventing contact with light.

[0042] According to one embodiment of this invention, the film coated tablet comprises;

[0043] Crystalline form-P or 1 or 3 or amorph of selexipag

[0044] D-mannitol

[0045] Corn starch

[0046] Coloring agent

[0047] According to one embodiment of this invention, the film coated tablet comprises;

[0048] Crystalline form-P or 1 or 3 or amorph of selexipag and

[0049] Hydroxypropyl methyl Cellulose

[0050] D-mannitol Corn starch

[0051] Low-substituted hydroxypropyl cellulose

[0052] Magnesium stearate.

[0053] According to one embodiment of this invention, the film coated tablet comprises;

[0054] Crystalline form-P or 1 or 3 or amorph of selexipag

[0055] Hydroxypropyl methyl Cellulose

[0056] D-mannitol

[0057] Corn starch

[0058] Low-substituted hydroxypropyl cellulose

[0059] Magnesium stearate.

[0060] Coloring agent.

[0061] According to one embodiment of this invention, the film coated tablet is obtained by wet granulation using solvent.

[0062] 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 a disintegrant, and then adding another half of a disintegrant and mixing again, c) Adding % of a filler and mixing, then adding the remaining part of the filler and mixing again, d) Adding a half of else a filler and mixing, and then adding another half of the filler and mixing, e) Granulating the dry mixture at step (d) with the solution step (a) and obtained wet granules.

[0063] 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 a disintegrant, and then adding another half of a disintegrant and mixing again, c) Adding % of a filler and mixing, then adding the remaining part of the filler and mixing again, d) Adding a half of else a filler and mixing, sieving into 0.8 mm and then adding another half of the filler and mixing. e) Granulating the dry mixture at step (d) with the solution step (a) and obtained wet granules, f) Drying the wet granules in an oven at 50 °C to the appropriate humidity value and then sieving, g) Adding at least one lubricant and then mixing, h) Compressing the mixture into tablets, i) Coating the tablets.

[0064] 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 hydroxypropyl methyl Cellulose 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 low substituted hydroxypropyl cellulose, and then adding another half of low substituted hydroxypropyl cellulose 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, sieving into 0.8 mm, 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 magnesium stearate and then mixing, h) Compressing the mixture into tablets, i) Coating the tablets.

[0065] Example 1: Example 2:

[0066] A process for example 1 or 2; a) Dissolving hydroxypropyl methyl Cellulose 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 low substituted hydroxypropyl cellulose, and then adding another half of low substituted hydroxypropyl cellulose 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, sieving into 0.8 mm, 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 magnesium stearate and then mixing, h) Compressing the mixture into tablets, i) Coating the tablets. Example 3:

[0067] A process for example 3; a) Dissolving hydroxypropyl methyl Cellulose 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 low substituted hydroxypropyl cellulose, and then adding another half of low substituted hydroxypropyl cellulose 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, sieving into 0.8 mm, 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 magnesium stearate and then mixing, i) Compressing the mixture into tablets, j) Coating the tablets.

Claims

CLAIMS ) A film coated tablet comprising selexipag or crystalline polymorph thereof and at least one filler wherein the tablet is obtained by wet granulation with geometric dilution method. ) The film coated tablet according to claim 1, wherein fillers are selected from the group comprising corn starch, microcrystalline cellulose, D-mannitol, lactose monohydrate, cellulose, cellulose acetate, compressible sugar, ethylcellulose, lactitol, lactose, magnesium oxide, maltodextrin, maltose, sorbitol, sucrose, talc or mixtures thereof. ) The film coated tablet according to claim 1, wherein fillers are D-mannitol and corn starch. ) The film coated tablet according to claim 3, wherein the amount of corn starch is between 25.0% and 45.0%, between 30.0% and 40.0% by weight of the total tablet and the amount of D- mannitol is between 45.0% and 58.0%, between 48.0% and 56.0% by weight of the total tablet. ) The film coated tablet according to claim 1, wherein selexipag is present in the form of amorph or form P or form 3 or form 1 or mixtures thereof. ) The film coated tablet according to claim 1, wherein the film coated tablet further comprising at least one pharmaceutically acceptable excipient selected from the group comprising disintegrants, binders, lubricants or mixtures thereof. ) The film coated tablet according to claim 6, wherein disintegrants are selected from the group comprising low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxymethyl starch or mixtures thereof. ) The film coated tablet according to claim 7, wherein the disintegrant is low-substituted hydroxypropyl cellulose. ) The film coated tablet according to claim 6, wherein 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.) The film coated tablet according to claim 9, wherein the binder is hydroxypropyl methyl cellulose. ) The film coated tablet according to any preceding claim, wherein the film coated tablet further comprising at least one coloring agent. ) The film coated tablet according to claim 11, wherein the film coated tablet comprising;Crystalline form-P or 1 or 3 or amorph of selexipagD-mannitolCorn starchColoring agent ) The film coated tablet according to claim 6, wherein the film coated tablet comprising;Crystalline form-P or 1 or 3 or amorph of selexipag andHydroxypropyl methyl CelluloseD-mannitolCorn starchLow-substituted hydroxypropyl celluloseMagnesium stearate. ) A process for preparing a film coated tablet comprising selexipag or crystalline polymorph thereof comprising 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 a disintegrant, and then adding another half of a disintegrant and mixing again, c) Adding % of a filler and mixing, then adding the remaining part of the filler and mixing again, d) Adding a half of else a filler and mixing, and then adding another half of the filler and mixing, e) Granulating the dry mixture at step (d) with the solution step (a) and obtained wet granules.

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