PHARMACEUTICAL COMPOSITION COMPRISING SELEXIPAG

Abstract

The present invention relates to pharmaceutical compositions comprising 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (selexipag, NS-304, ACT-293987) which are suitable for oral administration (p.o.).

Claims

1. A pharmaceutical composition comprising the compound of formula (I) in the amount of 80 to 170 mcg ##STR00003## or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof.

2. The pharmaceutical composition according to claim 1, further comprising one or more selected from the group consisting of: a) a filler; b) a disintegrant; c) a binder; and d) a lubricant.

3. The pharmaceutical composition according to claim 2, wherein the filler, if present, is one or more selected from the group consisting of: D-mannitol, maize starch, lactose, pregelatinized starch, dibasic calcium phosphate dihydrate (CaHPO4.2H2O), microcrystalline cellulose, and maltodextrin; the disintegrant, if present, is one or more selected from the group consisting of: low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, and cross-linked polyvinylpyrrolidone; the binder, if present, is one or more selected from the group consisting of: hydroxypropyl cellulose, sucrose, gelatine, starch, pregelatinized starch, alginic acid, sodium alginate, methyl cellulose, ethyl cellulose, hydroxy propyl methyl cellulose, polyvinyl pyrrolidinone, calcium carboxymethylcellulose, sodium carboxymethylcellulose, guar gum, clays, ion exchange resins and calcium silicate; the lubricant, if present, is one or more selected from the group consisting of: magnesium stearate, aluminium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl mono fatty acid, polyethylene glycol, hydrogenated cotton seed oil, castor seed oil, sucrose esters, calcium silicate and silicon dioxide.

4. The pharmaceutical composition according to claim 1, wherein (i) the filler is comprised in an amount from 11.5 to 145.0 mg; (ii) the disintegrant is comprised in an amount from 0.6 to 8.5 mg; (iii) the binder is comprised in an amount from 0.5 to 6.5 mg; and (iv) the lubricant is comprised in an amount from 0.2 to 2.5 mg.

5. The pharmaceutical composition according to claim 1, wherein (i) the filler is comprised in an amount from 12.0 to 45.0 mg; (ii) the disintegrant is comprised in an amount from 0.6 to 2.5 mg; (iii) the binder is comprised in an amount from 0.5 to 2.0 mg; and (iv) the lubricant is comprised in an amount from 0.2 to 0.7 mg.

6. The pharmaceutical composition according to claim 1, which comprises D-mannitol and maize starch; low substituted hydroxypropyl cellulose; hydroxypropyl cellulose; and magnesium stearate.

7. The pharmaceutical composition according to claim 6, which comprises D-mannitol in an amount from 7.0 to 90.0 mg; maize starch in an amount from 4.5 to 60.0 mg; low substituted hydroxypropyl cellulose in an amount from 0.6 to 9.0 mg; hydroxypropyl cellulose in an amount from 0.5 to 6.5 mg; and magnesium stearate is comprised in an amount from 0.2 to 2.5 mg.

8. The pharmaceutical composition according to claim 6, which comprises D-mannitol in an amount from 7.0 to 25.0 mg; maize starch in an amount from 4.5 to 20.0 mg; low substituted hydroxypropyl cellulose in an amount from 0.6 to 3.0 mg; hydroxypropyl cellulose in an amount from 0.5 to 2.0 mg; and magnesium stearate is comprised in an amount from 0.2 to 0.7 mg.

9. The pharmaceutical composition according to claim 1, which is in the form of a tablet.

10. The pharmaceutical composition according to claim 9, wherein the tablet is coated, the coating material comprising one or more selected from the group consisting of a plasticizer, a film former and a pigment.

11. The pharmaceutical composition according to claim 9, wherein the tablet is coated, the coating material comprising one or more selected from the group consisting of a plasticizer, a film former, a glidant and a pigment.

12. The pharmaceutical composition according to claim 9, wherein the tablet has a diameter of 1.5 to 4 mm.

13. (canceled)

14. The method according to claim 17, where the patient is a pediatric patient.

15. A method for treating a patient with hepatic impairment or a patient experiencing drug drug interaction with a CYP 2C8 inhibitor, comprising administering a pharmaceutical composition of the claim 1 to the patient.

16. (canceled)

17. A method treating or preventing pulmonary arterial hypertension (PAH) in a subject in need thereof, comprising administering a pharmaceutical composition of the claim 1 to the subject.

18. A method for preventing and/or treating ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pulmonary hypertension, pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance, connective tissue disease, chronic kidney diseases, diseases in which fibrosis of organs or tissues is involved, or respiratory diseases in a human subject in need thereof, comprising administering the pharmaceutical composition according to claim 1 to the human subject in need thereof.

19. The method according to claim 18, wherein the human subject is from ≥2 years to <18 years old.

20. The method according to claim 18, wherein the human subject is a patient with hepatic impairment or a patient experiencing drug drug interaction with CYP 2C8 inhibitors.

21. A process for manufacturing the pharmaceutical composition according to claim 1, comprising the steps of a) mixing the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof with a filler; b) adding a filler and a disintegrant to the blend of step a) and mixing it; c) wet-granulating the blend received from step (b) with a solution comprising the binder; d) drying and milling the granulate of step (c); e) lubricating the granulate with a lubricant in a suitable blender; and f) compressing the granulate into core tablets.

22. The method according to claim 18, wherein the chronic kidney disease is glomerulonephritis or diabetic nephropathy at any stage

Description

EXAMPLES

[0096] Abbreviations (as Used Herein and in the Description Above):

[0097] ERA endothelin receptor antagonist

[0098] IP receptor Prostacyclin receptor, also termed prostaglandin 12 receptor

[0099] mcg microgram

[0100] PAH pulmonary arterial hypertension

[0101] PDE-5 inhibitor phosphodiesterase type 5 inhibitor

[0102] PGI2 Prostaglandin I2

[0103] WHO world health organization

[0104] 1. Preparation of COMPOUND:

[0105] The preparation of selexipag (COMPOUND: 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide) is described in WO2002/088084. The preparation of polymorphic forms, i.e. the crystalline forms I, II, and III of the free base is disclosed in WO2010/150865; polymorphic forms of pharmaceutically acceptable salts are disclosed in WO2011/024874. COMPOUND was used in the following Examples and assays in form of the free base, especially crystals of polymorphic form I.

[0106] 2. Quantitative Composition of Selexipag Film-Coated Tablet

TABLE-US-00002 TABLE 2 Quantitative composition of selexipag film-coated tablet Ingredient Amount per tablet Dose strength 100 μg ACT-293987 0.10 mg D-Mannitol 9.07 mg Maize starch 6.04 mg Low substituted hydroxypropylcellulose 0.86 mg Hydroxypropylcellulose 0.68 mg Magnesium stearate 0.25 mg Core tablet weight 17.00 mg HPMC filmcoat and pigments 0.63 mg Carnauba wax Small quantity Coating weight 0.63 mg Total weight of film-coated tablet 17.63 mg

TABLE-US-00003 TABLE 3 Quantitative composition of selexipag film-coated tablet Ingredient Amount per tablet Dose strength 150 μg ACT-293987 0.90 mg D-Mannitol 9.07 mg Maize starch 6.04 mg Low substituted hydroxypropylcellulose 0.86 mg Hydroxypropylcellulose 0.68 mg Magnesium stearate 0.25 mg Core tablet weight 17.00 mg HPMC filmcoat and pigments 0.63 mg Carnauba wax Small quantity Coating weight 0.63 mg Total weight of film-coated tablet 17.63 mg

[0107] The film-coated tablet shown in Table 2 and 3 is a mini-tablet having a diameter of approximately 3 mm, which makes it easy to swallow for children.

[0108] 4. Manufacturing Process

[0109] i) Mixing

[0110] Selexipag and D-mannitol are blended in a suitable blender.

[0111] ii) Mixing

[0112] Maize starch and low-substituted hydroxypropylcellulose are then added to the blender. The mixture is blended.

[0113] iii) Wet Granulation

[0114] The blend is transferred into a fluid bed granulator/dryer and a solution of hydroxypropylcellulose in water is sprayed, maintaining the product at a temperature of approximately 30-35° C.

[0115] iv) Drying and Milling

[0116] The wet granulate is dried in the fluid bed dryer and milled.

[0117] v) Lubrication

[0118] The granulate is lubricated with magnesium stearate in a suitable blender.

[0119] vi) Compression

[0120] The final blend is compressed into core tablets.

[0121] vii) Coating

[0122] The tablet cores are loaded into the pan, and the coating suspension is sprayed until reaching the tablet conformity weight. The tablets are cooled until they are fully dried.

[0123] viii) Polishing

[0124] The film-coated tablets are polished using carnauba wax.

[0125] ix) Packaging

[0126] The film-coated tablets are packed in high-density polyethylene bottles with child-resistant polypropylene caps, and containing one desiccant.